Piperidine compounds which have useful pharmaceutical activity

ABSTRACT

A piperidine derivative having the formula (I): ##STR1## wherein R 1  and R 2 , which may be the same or different from each other, are (i) a not-substituted phenyl group or a phenyl group substituted by a halogen atom, trifluoromethyl group, a C 1-5  alkyl group or a C 1-5  alkoxyl group, (ii) a C 3-7  cycloalkyl group, (iii) pyridyl group or (iv) thienyl group, R 3  is (i) hydrogen atom, (ii) a halogen atom, (iii) a C 1-4  alkyl group or (iv) a C 1-4  alkoxyl group, R 4  is (i) hydrogen atom or (ii) a C 1-4  alkyl group. R 5  is (i) a not-substituted C 1-5  alkyl group or a C 1-5  alkyl group substituted by a halogen atom, (ii) phenyl group or (iii) thienyl group and Z is (i) a C 1-6  alkylene group, (ii) a C 2-6  alkenylene group or (iii) a C 3-6  alkynylene group or a pharmacologically acceptable salt thereof. According to the present invention, an anti-allergic agent and a therapeutic agent for ischemic heart disease without toxicity can be provided.

BACKGROUND OF THE INVENTION

The present invention relates to a piperidine derivative having theformula (I): ##STR2## wherein R¹ and R², which may be the same ordifferent from each other, are (i) a not-substituted phenyl group or aphenyl group substituted by a halogen atom, trifluoromethyl group, aC₁₋₅ alkyl group or a C₁₋₅ alkoxyl group, (ii) a C₃₋₇ cycloalkyl group,(iii) pyridyl group or (iv) thienyl group, R³ is (i) hydrogen atom, (ii)a halogen atom, (iii) a C₁₋₄ alkyl group or (iv) a C₁₋₄ alkoxyl group,R⁴ is (i) hydrogen atom or (ii) a C₁₋₄ alkyl group. R⁵ is (i) anot-substituted C₁₋₅ alkyl group or a C₁₋₅ alkyl group substituted by ahalogen atom, (ii) phenyl group or (iii) thienyl group and Z is (i) aC₁₋₆ alkylene group, (ii) a C₂₋₆ alkenylene group or (iii) a C₃₋₆alkynylene group or a pharmacologically acceptable salt thereof and acompound useful as an intermediate for synthesizing the compound havingthe formula (I).

Many factors participate in the onset or the exacerbation of allergicdiseases. Above all, the chemical mediators which are released withallergic reactions play particularly significant role.

Drugs for inhibiting the biosynthesis or release of chemical mediators,drugs for degradating or antagonizing chemical mediators and the likehave been studied and applied for clinical use as anti-allergic drugs.

There have been found many piperidine derivatives having anti-allergicaction. As compounds whose structure is partly similar to that of thecompound of the present invention, for example, there are thosecompounds described in Japanese Unexamined Patent Publication No.94962/1985, Japanese Unexamined Patent Publication No. 194068/1986,Japanese Unexamined Patent Publication No. 242574/1989, JapaneseUnexamined Patent Publication No. 25465/1990 and Japanese UnexaminedPatent Publication No. 108689/1990. However there are no compoundshaving sulfonamide group in molecule among the compounds disclosed inthe above-mentioned publications. Furthermore, as to the pharmacologicalaction of those compounds, there are no description that those compoundsmay have the inhibitory activity of mediator release.

An object of the present invention is to provide a novel compound havingthe inhibitory activity of mediator release, antihistaminic activity andthe like, an anti-allergic agent comprising the same as an effectiveingredient, a treatment agent for ischemic heart disease comprising thesame as an effective ingredient and an intermediate compound forsynthesizing the same.

This and the other objects of the present invention will become apparentfrom the description hereinafter.

SUMMARY OF THE INVENTION

It has now been found that a piperizine derivative having sulfonamidegroup in its molecule shows the inhibitory activity of mediator release,antihistaminic activity and therapeutic activity for ischemic heartdisease.

That is, the present invention relates to a piperidine derivative havingthe formula (I): ##STR3## wherein R¹ and R², which may be the same ordifferent from each other, are (i) a not-substituted phenyl group or aphenyl group substituted by a halogen atom, trifluoromethyl group, aC₁₋₅ alkyl group or a C₁₋₅ alkoxyl group, (ii) a C₃₋₇ cycloalkyl group,(iii) pyridyl group or (iv) thienyl group, R³ is (i) hydrogen atom, (ii)a halogen atom, (iii) a C₁₋₄ alkyl group or (iv) a C₁₋₄ alkoxyl group,R⁴ is (i) hydrogen atom or (ii) a C₁₋₄ alkyl group, R⁵ is (i) anot-substituted C₁₋₅ alkyl group or a C₁₋₅ alkyl group substituted by ahalogen atom, (ii) phenyl group or (iii) thienyl group and Z is (i) aC₁₋₆ alkylene group, (ii) a C₂₋₆ alkenylene group or (iii) a C₃₋₆alkynylene group or a pharmacologically acceptable salt thereof, ananti-allergic agent comprising as an effective ingredient theabove-mentioned piperidine derivative or a pharmacologically acceptablesalt thereof, a therapeutic agent for ischemic heart disease comprisingas an effective ingredient the above-mentioned piperidine derivative ora pharmacologically acceptable salt thereof, a piperidine derivativehaving the formula (II): ##STR4## wherein R¹ and R², which may be thesame or different from each other, are (i) a not-substituted phenylgroup or a phenyl group substituted by a halogen atom, trifluoromethylgroup, a C₁₋₅ alkyl group or a C₁₋₅ alkoxyl group, (ii) a C₃₋₇cycloalkyl group, (iii) pyridyl group or (iv) thienyl group, R³ is (i)hydrogen atom, (ii) a halogen atom, (iii) a C₁₋₄ alkyl group or (iv) aC₁₋₄ alkoxyl group, and Z is (i) a C₁₋₆ alkylene group, (ii) a C₂₋₆alkenylene group or (iii) a C₃₋₆ alkynylene group, which is anintermediate for preparing the above-mentioned piperidine derivative,and a piperidine derivative having the formula (III): ##STR5## whereinR¹ and R², which may be the same or different from each other, are (i) anot-substituted phenyl group or a phenyl group substituted by a halogenatom, trifluoromethyl group, a C₁₋₅ alkyl group or a C₁₋₅ alkoxyl group,(ii) a C₃₋₇ cycloalkyl group, (iii) pyridyl group or (iv) thienyl group,R³ is (i) hydrogen atom, (ii) a halogen atom, (iii) a C₁₋₄ alkyl groupor (iv) a C₁₋₄ alkoxyl group, and Z is (i) a C₁₋₆ alkylene group, (ii) aC₂₋₆ alkenylene group or (iii) a C₃₋₆ alkynylene group, which is anintermediate for preparing the above-mentioned piperidine derivative.

DETAILED DESCRIPTION

The piperidine derivative having the formula (I), (II) or (III) areexplained below.

As substituted phenyl groups represented by R¹ and R² in theabove-mentioned formula (I), (II) or (III), there are, for example,phenyl groups substituted by one or more halogen atoms, such as2-fluoro-, 3-fluoro-, 4-fluoro-, 2,4-difluoro-, 2,5-difluoro-,3,4-difluoro-, 2-chloro-, 3-chloro-, 4-chloro-, 3,4-dichloro-, 4-bromo-and 4-iodo- phenyl groups, phenyl groups substituted by trifluoromethylgroup, such as 2-trifluoromethyl-, 3-trifluoromethyl- and4-trifluoromethyl- phenyl groups, phenyl groups substituted by one ormore straight chain or branched chain C₁₋₅ alkyl groups, such as2-methyl-, 3-methyl-, 4-methyl-, 2,4-dimethyl-, 3,4-dimethyl-, 4-ethyl-,4-n-propyl-, 4-isopropyl-, 4-n-butyl-, 4-isobutyl-, 4-tert-butyl- and4-n-pentyl- phenyl groups and phenyl groups substituted by one or morestraight chain or branched chain C₁₋₅ alkoxyl group, such as 4-methoxy-,3,4-dimethoxy-, 4-ethoxy-, 4-n-propoxy-, 4-isopropoxy-, 4-n-butoxy-,4-isobutoxy- and 4 -n-pentyloxy- phenyl groups.

As cycloalkyl groups represented by R¹ and R², there are, for example,C₃₋₇ cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

As pyridyl groups represented by R¹ and R², there are, for example,pyridyl groups such as 2-pyridyl, 3-pyridyl and 4-pyridyl.

As thienyl groups represented by R¹ and R², there are, for example,thienyl groups such as 2-thienyl and 3-thienyl.

As R³, there are, for example, hydrogen atom, halogen atoms such asfluorine, chlorine, bromine and iodine, C₁₋₄ alkyl groups such asmethyl, ethyl, n-propyl, isopropyl and butyl, C₁₋₄ alkoxyl groups suchas methoxy, ethoxy, n-propoxy, isopropoxy and butoxy and the like.

As R⁴, there are, for example, hydrogen atom, C₁₋₄ alkyl groups such asmethyl, ethyl, n-propyl, isopropyl and butyl and the like.

As R⁵, there are, for example, C₁₋₅ alkyl groups which may besubstituted by one or more halogen atoms such as methyl, ethyl,n-propyl, isopropyl, n-butyl, n-pentyl, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, trichloromethyl, 2,2,2-trifluoroethyl and2-chloroethyl, phenyl group, thienyl groups such as 2-thienyl and3-thienyl and the like.

As Z, there are, for example, straight chain or branched chain C₁₋₆alkylene groups such as methylene, ethylene, trimethylene,1-methylethylene, 2-methylethylene, tetramethylene,1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene,1-ethylethylene, pentamethylene, 1-methyltetramethylene,2-methyltetramethylene, 3-methyltetramethylene, 4-methyltetramethylene,1,1-dimethyltrimethylene and hexamethylene, straight chain or branchedchain C₂₋₆ alkenylene groups such as vinylene, 1-propenylene,1-butenylene, 2-butenylene, 2-methylprop-1-enylene,3-methylprop-1-enylene and 2-pentenylene, straight chain or branchedchain C₃₋₆ alkynylene groups such as 1-propynylene, 1-butynylene,2-butynylene, 3-methylprop-1-ynylene and 2-pentynylene and the like.

When there are one or more asymmetric carbon atoms in the compoundshaving the formula (I), (II) or (III), a racemate, a diastereoisomer andeach optical isomer thereof are all included in the present invention.If there are geometrical isomers, (E)-form, (Z)-form and the mixturethereof are also included in the present invention.

As concrete examples of the piperidine derivatives of the presentinvention having the formula (I), the piperidine derivative wherein R¹,R², Z, R³, R⁴ and R⁵ are respectively the groups shown in the followingTable 1 can be exemplified.

However, it is to be understood that the present invention is notlimited to those compounds.

                                      TABLE 1                                     __________________________________________________________________________     ##STR6##                                        (I)                           No.                                                                              R.sup.1                                                                              R.sup.2                                                                              Z                 R.sup.3                                                                            ##STR7##                             __________________________________________________________________________     1 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      CH.sub.2          H    2-NHSO.sub.2 CH.sub.3                  2 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.2  H    2-NHSO.sub.2 CH.sub.3                  3 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                  4 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H    3-NHSO.sub.2 CH.sub.3                  5 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H    4-NHSO.sub.2 CH.sub.3                  6 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H    2-NHSO.sub.2 C.sub.2 H.sub.5           7 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H    2-NHSO.sub.2 C.sub.3 H.sub.7           8 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H    2-NHSO.sub.2 CF.sub.3                  9 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H                                                                                   ##STR8##                             10 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H                                                                                   ##STR9##                             11 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H    2-N(CH.sub.3)SO.sub.2 CH.sub.3        12 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  5-F  2-NHSO.sub.2 CH.sub.3                 13 C.sub.6 H.sub. 5                                                                     C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  4-Cl 2-NHSO.sub.2 CH.sub.3                 14 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  5-Cl 2-NHSO.sub.2 CH.sub.3                 15 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  3-CH.sub.3                                                                         2-NHSO.sub.2 CH.sub.3                 16 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  4-CH.sub.3                                                                         2-NHSO.sub.2 CH.sub.3                 17 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  5-CH.sub.3                                                                         2-NHSO.sub.2 CH.sub.3                 18 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  4-OCH.sub.3                                                                        2-NHSO.sub.2 CH.sub.3                 19 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                       ##STR10##        H    2-NHSO.sub.2 CH.sub.3                 20 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                       ##STR11##        H    2-NHSO.sub.2 CH.sub.3                 21 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                       ##STR12##        H    2-NHSO.sub.2 CH.sub.3                 22 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.4  H    2-NHSO.sub.2 CH.sub.3                 23 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 24 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 25 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      CH.sub.2 CCCH.sub.2                                                                             H    2-NHSO.sub.2 CH.sub.3                 26 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                       ##STR13##        H    2-NHSO.sub.2 CH.sub.3                 27 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                       ##STR14##        H    2-NHSO.sub.2 CH.sub.3                 28 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.5  H    2-NHSO.sub. 2 CH.sub.3                29 C.sub.6 H.sub.5                                                                      4-FC.sub.6 H.sub.4                                                                   (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 30 C.sub.6 H.sub.5                                                                      2,4-F.sub.2 C.sub.6 H.sub.3                                                          (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 31 C.sub.6 H.sub.5                                                                      2-ClC.sub.6 H.sub.4                                                                  (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 32 C.sub.6 H.sub.5                                                                      4-ClC.sub.6 H.sub.4                                                                  (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 33 C.sub.6 H.sub.5                                                                      3-CF.sub.3 C.sub.6 H.sub.4                                                           (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 34 C.sub.6 H.sub.5                                                                      4-CF.sub.3 C.sub.6 H.sub.4                                                           (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 35 C.sub.6 H.sub.5                                                                      2-CH.sub.3 C.sub.6 H.sub.4                                                           (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 36 C.sub.6 H.sub.5                                                                      3-CH.sub.3 C.sub.6 H.sub.4                                                           (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 37 C.sub.6 H.sub.5                                                                      4-CH.sub.3 C.sub.6 H.sub.4                                                           (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 38 C.sub.6 H.sub.5                                                                      4-C.sub.2 H.sub.5 C.sub.6 H.sub.4                                                    (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 39 C.sub.6 H.sub.5                                                                      4-CH.sub.3 OC.sub.6 H.sub.4                                                          (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 40 4-FC.sub.6 H.sub.4                                                                   4-FC.sub.6 H.sub.4                                                                   (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 41 4-ClC.sub.6 H.sub.4                                                                  4-ClC.sub.6 H.sub.4                                                                  (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 42 4-CH.sub.3 C.sub.6 H.sub.4                                                           4-CH.sub.3 C.sub.6 H.sub.4                                                           (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 43 4-CH.sub.3 OC.sub.6 H.sub.4                                                          4-CH.sub.3 OC.sub.6 H.sub.4                                                          (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 44 cyclopentyl                                                                          C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 45 cyclohexyl                                                                           C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 46 2-pyridyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 47 2-pyridyl                                                                            C.sub.6 H.sub.5                                                                       ##STR15##        H    2-NHSO.sub.2 CH.sub.3                 48 2-pyridyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 49 2-pyridyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 50 2-pyridyl                                                                            4-ClC.sub.6 H.sub.4                                                                  (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 51 3-pyridyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 52 3-pyridyl                                                                            C.sub.6 H.sub.5                                                                       ##STR16##        H    2-NHSO.sub.2 CH.sub.3                 53 3-pyridyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 54 3-pyridyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 55 4-pyridyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 56 4-pyridyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 57 4-pyridyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 58 2-thienyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.2  H    2-NHSO.sub.2 CH.sub.3                 59 2-thienyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 60 2-thienyl                                                                            C.sub.6 H.sub.5                                                                       ##STR17##        H    2-NHSO.sub.2 CH.sub.3                 61 2-thienyl                                                                            C.sub.6 H.sub.5                                                                       ##STR18##        H    2-NHSO.sub.2 CH.sub.3                 62 2-thienyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.4  H    2-NHSO.sub.2 CH.sub.3                 63 2-thienyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 64 2-thienyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub. 3                65 2-thienyl                                                                            C.sub.6 H.sub.5                                                                       ##STR19##        H    2-NHSO.sub.2 CH.sub.3                 66 2-thienyl                                                                            C.sub.6 H.sub.5                                                                       ##STR20##        H    2-NHSO.sub.2 CH.sub.3                 67 3-thienyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.2  H    2-NHSO.sub.2 CH.sub.3                 68 3-thienyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 69 3-thienyl                                                                            C.sub.6 H.sub.5                                                                       ##STR21##        H    2-NHSO.sub.2 CH.sub.3                 70 3-thienyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.4  H    2-NHSO.sub.2 CH.sub.3                 71 3-thienyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 72 3-thienyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 73 3-thienyl                                                                            C.sub.6 H.sub.5                                                                       ##STR22##        H    2-NHSO.sub.2 CH.sub.3                 74 2-thienyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.2  H    2-NHSO.sub.2 CH.sub.3                 75 2-thienyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 76 2-thienyl                                                                            2-thienyl                                                                             ##STR23##        H    2-NHSO.sub.2 CH.sub.3                 77 2-thienyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.4  H    2-NHSO.sub.2 CH.sub.3                 78 2-thienyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 79 2-thienyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 80 2-thienyl                                                                            2-thienyl                                                                             ##STR24##        H    2-NHSO.sub.2 CH.sub.3                 81 2-thienyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.2  H    2-NHSO.sub.2 CH.sub.3                 82 2-thienyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 83 2-thienyl                                                                            3-thienyl                                                                             ##STR25##        H    2-NHSO.sub. 2 CH.sub.3                84 2-thienyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.4  H    2-NHSO.sub.2 CH.sub.3                 85 2-thienyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 86 2-thienyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 87 2-thienyl                                                                            3-thienyl                                                                             ##STR26##        H    2-NHSO.sub.2 CH.sub.3                 88 3-thienyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.2  H    2-NHSO.sub.2 CH.sub.3                 89 3-thienyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 90 3-thienyl                                                                            3-thienyl                                                                             ##STR27##        H    2-NHSO.sub.2 CH.sub.3                 91 3-thienyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.4  H    2-NHSO.sub.2 CH.sub.3                 92 3-thienyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 93 3-thienyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 94 3-thienyl                                                                            3-thienyl                                                                             ##STR28##        H    2-NHSO.sub.2 CH.sub.3                 95 3-thienyl                                                                            3-thienyl                                                                             ##STR29##        H    2-NHSO.sub.2 CH.sub.3                 96 2-pyridyl                                                                            2-pyridyl                                                                            (CH.sub.2).sub.2  H    2-NHSO.sub.2 CH.sub.3                 97 2-pyridyl                                                                            2-pyridyl                                                                            (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 98 2-pyridyl                                                                            2-pyridyl                                                                             ##STR30##        H    2-NHSO.sub.2 CH.sub.3                 99 2-pyridyl                                                                            2-pyridyl                                                                            (CH.sub.2).sub.4  H    2-NHSO.sub.2 CH.sub.3                 100                                                                              2-pyridyl                                                                            2-pyridyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 101                                                                              2-pyridyl                                                                            2-pyridyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 102                                                                              2-pyridyl                                                                            2-pyridyl                                                                             ##STR31##        H    2-NHSO.sub.2 CH.sub.3                 103                                                                              3-pyridyl                                                                            3-pyridyl                                                                            (CH.sub.2).sub.2  H    2-NHSO.sub. 2 CH.sub.3                104                                                                              3-pyridyl                                                                            3-pyridyl                                                                            (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 105                                                                              3-pyridyl                                                                            3-pyridyl                                                                             ##STR32##        H    2-NHSO.sub.2 CH.sub.3                 106                                                                              3-pyridyl                                                                            3-pyridyl                                                                            (CH.sub.2).sub.4  H    2-NHSO.sub.2 CH.sub.3                 107                                                                              3-pyridyl                                                                            3-pyridyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 108                                                                              3-pyridyl                                                                            3-pyridyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 109                                                                              3-pyridyl                                                                            3-pyridyl                                                                             ##STR33##        H    2-NHSO.sub.2 CH.sub.3                 110                                                                              2-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.2  H    2-NHSO.sub.2 CH.sub.3                 111                                                                              2-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 112                                                                              2-pyridyl                                                                            2-thienyl                                                                             ##STR34##        H    2-NHSO.sub.2 CH.sub.3                 113                                                                              2-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.4  H    2-NHSO.sub.2 CH.sub.3                 114                                                                              2-pyridyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 115                                                                              2-pyridyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 116                                                                              2-pyridyl                                                                            2-thienyl                                                                             ##STR35##        H    2-NHSO.sub.2 CH.sub.3                 117                                                                              2-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.2  H    2-NHSO.sub.2 CH.sub.3                 118                                                                              2-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 119                                                                              2-pyridyl                                                                            3-thienyl                                                                             ##STR36##        H    2-NHSO.sub.2 CH.sub.3                 120                                                                              2-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.4  H    2-NHSO.sub.2 CH.sub.3                 121                                                                              2-pyridyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 122                                                                              2-pyridyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 123                                                                              2-pyridyl                                                                            3-thienyl                                                                             ##STR37##        H    2-NHSO.sub.2 CH.sub.3                 124                                                                              3-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.2  H    2-NHSO.sub.2 CH.sub.3                 125                                                                              3-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 126                                                                              3-pyridyl                                                                            2-thienyl                                                                             ##STR38##        H    2-NHSO.sub.2 CH.sub.3                 127                                                                              3-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.4  H    2-NHSO.sub.2 CH.sub.3                 128                                                                              3-pyridyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 129                                                                              3-pyridyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 130                                                                              3-pyridyl                                                                            2-thienyl                                                                             ##STR39##        H    2-NHSO.sub.2 CH.sub.3                 131                                                                              3-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.2  H    2-NHSO.sub.2 CH.sub.3                 132                                                                              3-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 133                                                                              3-pyridyl                                                                            3-thienyl                                                                             ##STR40##        H    2-NHSO.sub.2 CH.sub.3                 134                                                                              3-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.4  H    2-NHSO.sub.2 CH.sub.3                 135                                                                              3-pyridyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 136                                                                              3-pyridyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 137                                                                              3-pyridyl                                                                            3-thienyl                                                                             ##STR41##        H    2-NHSO.sub.2 CH.sub.3                 138                                                                              4-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.2  H    2-NHSO.sub.2 CH.sub.3                 139                                                                              4-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 140                                                                              4-pyridyl                                                                            2-thienyl                                                                             ##STR42##        H    2-NHSO.sub.2 CH.sub.3                 141                                                                              4-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.4  H    2-NHSO.sub.2 CH.sub.3                 142                                                                              4-pyridyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 143                                                                              4-pyridyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 144                                                                              4-pyridyl                                                                            2-thienyl                                                                             ##STR43##        H    2-NHSO.sub.2 CH.sub.3                 145                                                                              4-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.2  H    2-NHSO.sub.2 CH.sub.3                 146                                                                              4-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.3  H    2-NHSO.sub.2 CH.sub.3                 147                                                                              4-pyridyl                                                                            3-thienyl                                                                             ##STR44##        H    2-NHSO.sub.2 CH.sub.3                 148                                                                              4-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.4  H    2-NHSO.sub.2 CH.sub.3                 149                                                                              4-pyridyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 150                                                                              4-pyridyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                H    2-NHSO.sub.2 CH.sub.3                 151                                                                              4-pyridyl                                                                            3-thienyl                                                                             ##STR45##        H    2-NHSO.sub.2 CH.sub.3                 __________________________________________________________________________

The present invention also includes a pharmacologically accepatable saltof the piperidine derivatives having the formula (I).

As such salts, there are, for example, a salt with hydrohalogenic acidsuch as hydrofluoric acid, hydrochloric acid, hydrobromic acid orhydroiodic acid, a salt with an inorganic acid such as nitric acid,perchloric acid, sulfuric acid, phosphoric acid or carbonic acid, a saltwith a lower alkyl sulfonic acid such as methanesulfonic acid,trifluoromethanesulfonic acid or ethanesulfonic acid, a salt with anarylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonicacid, a salt with an organic acid such as fumaric acid, succinic acid,citric acid, tartaric acid, oxalic acid or maleic acid, a salt with anamino acid such as glycine, alanine, glutamic acid or aspartic acid andthe like.

When R⁴ in the formula (I) is hydrogen atom, a salt with alkaline metalsuch as sodium or pottasium can be exemplified.

As concrete examples of the piperidine derivatives of the presentinvention having the formula (II) or (III), the piperidine derivativeswherein R¹, R², Z and R³ in the formula (II) or (III) are respectivelythe groups shown in the following Table 2 can be exemplified.

However, it is to be understood that the present invention is notlimited to those compounds.

                                      TABLE 2                                     __________________________________________________________________________     ##STR46##                                                                     ##STR47##                                                                                                             position                                                                      substituted                                                                   by NO.sub.2 in                                                                (II) or NH.sub.2                     No.                                                                              R.sup.1                                                                              R.sup.2                                                                              Z                  R.sup.3                                                                            in (III)                             __________________________________________________________________________     1 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      CH.sub.2           H    2-                                    2 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.2   H    2-                                    3 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   H    2-                                    4 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   H    3-                                    5 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   H    4-                                    6 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   5-F  2-                                    7 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   4-Cl 2-                                    8 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   3-CH.sub.3                                                                         2-                                    9 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   4-CH.sub.3                                                                         2-                                   10 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   5-CH.sub.3                                                                         2-                                   11 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   4-OCH.sub.3                                                                        2-                                   12 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                       ##STR48##         H    2-                                   13 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                       ##STR49##         H    2-                                   14 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                       ##STR50##         H    2-                                   15 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.4   H    2-                                   16 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   17 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   18 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      CH.sub.2 CCCH.sub.2                                                                              H    2-                                   19 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                       ##STR51##         H    2-                                   20 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                       ##STR52##         H    2-                                   21 C.sub.6 H.sub.5                                                                      C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.5   H    2-                                   22 C.sub.6 H.sub.5                                                                      4-FC.sub.6 H.sub.4                                                                   (CH.sub.2).sub.3   H    2-                                   23 C.sub.6 H.sub.5                                                                      2,4-F.sub.2 C.sub.6 H.sub.3                                                          (CH.sub.2).sub.3   H    2-                                   24 C.sub.6 H.sub.5                                                                      2-ClC.sub.6 H.sub.4                                                                  (CH.sub.2).sub.3   H    2-                                   25 C.sub.6 H.sub.5                                                                      4-ClC.sub.6 H.sub.4                                                                  (CH.sub.2).sub.3   H    2-                                   26 C.sub.6 H.sub.5                                                                      3-CF.sub.3 C.sub.6 H.sub.4                                                           (CH.sub.2).sub.3   H    2-                                   27 C.sub.6 H.sub.5                                                                      4-CF.sub.3 C.sub.6 H.sub.4                                                           (CH.sub.2).sub.3   H    2-                                   28 C.sub.6 H.sub.5                                                                      2-CH.sub.3 C.sub.6 H.sub.4                                                           (CH.sub.2).sub.3   H    2-                                   29 C.sub.6 H.sub.5                                                                      3-CH.sub.3 C.sub.6 H.sub.4                                                           (CH.sub.2).sub.3   H    2-                                   30 C.sub.6 H.sub.5                                                                      4-CH.sub.3 C.sub.6 H.sub.4                                                           (CH.sub.2).sub.3   H    2-                                   31 C.sub.6 H.sub.5                                                                      4-C.sub.2 H.sub.5 C.sub.6 H.sub.4                                                    (CH.sub.2).sub.3   H    2-                                   32 C.sub.6 H.sub.5                                                                      4-CH.sub.3 OC.sub.6 H.sub.4                                                          (CH.sub.2).sub.3   H    2-                                   33 4-FC.sub.6 H.sub.4                                                                   4-FC.sub.6 H.sub.4                                                                   (CH.sub.2).sub.3   H    2-                                   34 4-ClC.sub.6 H.sub.4                                                                  4-ClC.sub.6 H.sub.4                                                                  (CH.sub.2).sub.3   H    2-                                   35 4-CH.sub.3 C.sub.6 H.sub.4                                                           4-CH.sub.3 C.sub.6 H.sub.4                                                           (CH.sub.2).sub.3   H    2-                                   36 4-CH.sub.3 OC.sub.6 H.sub.4                                                          4-CH.sub.3 OC.sub.6 H.sub.4                                                          (CH.sub.2).sub.3   H    2-                                   37 cyclopentyl                                                                          C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   H    2-                                   38 cyclohexyl                                                                           C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   H    2-                                   39 2-pyridyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   H    2-                                   40 2-pyridyl                                                                            C.sub.6 H.sub.5                                                                       ##STR53##         H    2-                                   41 2-pyridyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   42 2-pyridyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   43 2-pyridyl                                                                            4-ClC.sub.6 H.sub.4                                                                  (CH.sub.2).sub.3   H    2-                                   44 3-pyridyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   H    2-                                   45 3-pyridyl                                                                            C.sub.6 H.sub.5                                                                       ##STR54##         H    2-                                   46 3-pyridyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   47 3-pyridyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   48 4-pyridyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   H    2-                                   49 4-pyridyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   50 4-pyridyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   51 2-thienyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.2   H    2-                                   52 2-thienyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   H    2-                                   53 2-thienyl                                                                            C.sub.6 H.sub.5                                                                       ##STR55##         H    2-                                   54 2-thienyl                                                                            C.sub.6 H.sub.5                                                                       ##STR56##         H    2-                                   55 2-thienyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.4   H    2-                                   56 2-thienyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   57 2-thienyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   58 2-thienyl                                                                            C.sub.6 H.sub.5                                                                       ##STR57##         H    2-                                   59 2-thienyl                                                                            C.sub.6 H.sub.5                                                                       ##STR58##         H    2-                                   60 3-thienyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.2   H    2-                                   61 3-thienyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.3   H    2-                                   62 3-thienyl                                                                            C.sub.6 H.sub.5                                                                       ##STR59##         H    2-                                   63 3-thienyl                                                                            C.sub.6 H.sub.5                                                                      (CH.sub.2).sub.4   H    2-                                   64 3-thienyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   65 3-thienyl                                                                            C.sub.6 H.sub.5                                                                      CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   66 3-thienyl                                                                            C.sub.6 H.sub.5                                                                       ##STR60##         H    2-                                   67 2-thienyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.2   H    2-                                   68 2-thienyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.3   H    2-                                   69 2-thienyl                                                                            2-thienyl                                                                             ##STR61##         H    2-                                   70 2-thienyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.4   H    2-                                   71 2-thienyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   72 2-thienyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   73 2-thienyl                                                                            2-thienyl                                                                             ##STR62##         H    2-                                   74 2-thienyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.2   H    2-                                   75 2-thienyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.3   H    2-                                   76 2-thienyl                                                                            3-thienyl                                                                             ##STR63##         H    2-                                   77 2-thienyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.4   H    2-                                   78 2-thienyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   79 2-thienyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   80 2-thienyl                                                                            3-thienyl                                                                             ##STR64##         H    2-                                   81 3-thienyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.2   H    2-                                   82 3-thienyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.3   H    2-                                   83 3-thienyl                                                                            3-thienyl                                                                             ##STR65##         H    2-                                   84 3-thienyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.4   H    2-                                   85 3-thienyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub. 2 [(E) form]                                                                H    2-                                   86 3-thienyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   87 3-thienyl                                                                            3-thienyl                                                                             ##STR66##         H    2-                                   88 3-thienyl                                                                            3-thienyl                                                                             ##STR67##         H    2-                                   89 2-pyridyl                                                                            2-pyridyl                                                                            (CH.sub.2).sub.2   H    2-                                   90 2-pyridyl                                                                            2-pyridyl                                                                            (CH.sub.2).sub.3   H    2-                                   91 2-pyridyl                                                                            2-pyridyl                                                                             ##STR68##         H    2-                                   92 2-pyridyl                                                                            2-pyridyl                                                                            (CH.sub.2).sub.4   H    2-                                   93 2-pyridyl                                                                            2-pyridyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   94 2-pyridyl                                                                            2-pyridyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   95 2-pyridyl                                                                            2-pyridyl                                                                             ##STR69##         H    2-                                   96 3-pyridyl                                                                            3-pyridyl                                                                            (CH.sub.2).sub.2   H    2-                                   97 3-pyridyl                                                                            3-pyridyl                                                                            (CH.sub.2).sub.3   H    2-                                   98 3-pyridyl                                                                            3-pyridyl                                                                             ##STR70##         H    2-                                   99 3-pyridyl                                                                            3-pyridyl                                                                            (CH.sub.2).sub.4   H    2-                                   100                                                                              3-pyridyl                                                                            3-pyridyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   101                                                                              3-pyridyl                                                                            3-pyridyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   102                                                                              3-pyridyl                                                                            3-pyridyl                                                                             ##STR71##         H    2-                                   103                                                                              2-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.2   H    2-                                   104                                                                              2-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.3   H    2-                                   105                                                                              2-pyridyl                                                                            2-thienyl                                                                             ##STR72##         H    2-                                   106                                                                              2-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.4   H    2-                                   107                                                                              2-pyridyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   108                                                                              2-pyridyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   109                                                                              2-pyridyl                                                                            2-thienyl                                                                             ##STR73##         H    2-                                   110                                                                              2-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.2   H    2-                                   111                                                                              2-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.3   H    2-                                   112                                                                              2-pyridyl                                                                            3-thienyl                                                                             ##STR74##         H    2-                                   113                                                                              2-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.4   H    2-                                   114                                                                              2-pyridyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   115                                                                              2-pyridyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   116                                                                              2-pyridyl                                                                            3-thienyl                                                                             ##STR75##         H    2-                                   117                                                                              3-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.2   H    2-                                   118                                                                              3-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.3   H    2-                                   119                                                                              3-pyridyl                                                                            2-thienyl                                                                             ##STR76##         H    2-                                   120                                                                              3-pyridyl                                                                            2-thienyl                                                                            (CH.sub. 2).sub.4  H    2-                                   121                                                                              3-pyridyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   122                                                                              3-pyridyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   123                                                                              3-pyridyl                                                                            2-thienyl                                                                             ##STR77##         H    2-                                   124                                                                              3-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.2   H    2-                                   125                                                                              3-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.3   H    2-                                   126                                                                              3-pyridyl                                                                            3-thienyl                                                                             ##STR78##         H    2-                                   127                                                                              3-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.4   H    2-                                   128                                                                              3-pyridyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   129                                                                              3-pyridyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   130                                                                              3-pyridyl                                                                            3-thienyl                                                                             ##STR79##         H    2-                                   131                                                                              4-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.2   H    2-                                   132                                                                              4-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.3   H    2-                                   133                                                                              4-pyridyl                                                                            2-thienyl                                                                             ##STR80##         H    2-                                   134                                                                              4-pyridyl                                                                            2-thienyl                                                                            (CH.sub.2).sub.4   H    2-                                   135                                                                              4-pyridyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   136                                                                              4-pyridyl                                                                            2-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(Z) form]                                                                 H    2-                                   137                                                                              4-pyridyl                                                                            2-thienyl                                                                             ##STR81##         H    2-                                   138                                                                              4-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.2   H    2-                                   139                                                                              4-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.3   H    2-                                   140                                                                              4-pyridyl                                                                            3-thienyl                                                                             ##STR82##         H    2-                                   141                                                                              4-pyridyl                                                                            3-thienyl                                                                            (CH.sub.2).sub.4   H    2-                                   142                                                                              4-pyridyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub.2 [(E) form]                                                                 H    2-                                   143                                                                              4-pyridyl                                                                            3-thienyl                                                                            CH.sub.2 CHCHCH.sub. 2 [(Z) form]                                                                H    2-                                   144                                                                              4-pyridyl                                                                            3-thienyl                                                                             ##STR83##         H    2-                                   __________________________________________________________________________

The process for preparing the piperidine derivatives having the formula(I), (II) or (III) are explained below.

The piperidine derivatives having the formula (I), (II) or (III) can beprepared according to the following processes. ##STR84##

In the above-mentioned formulae, R¹, R², R³, R⁵ and Z are the same asabove-defined, R⁶ is a C₁₋₄ alkyl group, X is chlorine, bromine oriodine and Y is chlorine or R⁵ --SO₂ --O-- where in R⁵ is the same asabove-defined.

The above-mentioned processes are described further detailedly in thefollowings.

PROCESS A-1

The desired compound having the formula (II) can be prepared bydehydrating reaction of the compound having the formula (IV) and thecompound having the formula (V) in the presence of concentrated sulfuricacid in an inactive solvent.

The inactive solvents usable in the present reaction are notparticularly limited, if the solvents do not considerably inhibit thistype of reaction. As such solvents, for example, benzene, toluene,xylene and the like are preferable.

In the present reaction, 0.5 to 2 moles of the compound having theformula (V) is used per mole of the compound having the formula (IV).

Although concentrated sulfuric acid is generally used in an excessamount, 2 to 20 moles of concentrated sulfuric acid is preferably usedper mole of the compound having the formula (IV).

The reaction temperature can be suitably selected in the range of from50° C. to the boiling point of the used solvent. The reaction time canbe suitably selected in the range of from 1 to 10 hours.

PROCESS A-2

The desired compound having the formula (II) can be prepared by reactingthe compound having the formula (VI) and the compound having the formula(V) in the presence of a base in an inactive solvent.

The inactive solvents usable in the present reaction are notparticularly limited, if the solvents do not considerably inhibit thistype of reaction. As such solvents, for example, methyl ethyl ketone,methyl isobutyl ketone, tetrahydrofuran, 1,2-dichloroethane, benzene,toluene, dimethylformamide and the like are preferable.

Bases usable in the present reaction are not particularly limited, ifthey usually act as bases. As such bases, for example, inorganic basessuch as sodium carbonate, potassium carbonate, sodium bicarbonate andpotassium bicarbonate, organic bases of tertiary amine such astriethylamine, N,N-diisopropylethylamine and pyridine and the like arepreferable.

In the present reaction, 0.5 to 2 moles of the compound having theformula (V) is used per mole of the compound having the formula (VI).

The base is used in an amount of at least equivalent mole, generally 1to 5 moles per mole of the compound having the formula (VI).

The reaction temperature can be suitably selected in the range of from60° C. to the boiling point of the used solvent. The reaction time canbe suitably selected in the range of from 0.5 to 100 hours.

PROCESS A-3

The desired compound having the formula (II) can be prepared by reactingthe compound having the formula (VII) and the compound having theformula (VIII) in the presence of a base in an inactive solvent.

The inactive solvents usable in the present reaction are notparticularly limited, if the solvents do not considerably inhibit thistype of reaction. As such solvents, for example, methyl alcohol, ethylalcohol, propyl alcohol, methyl ethyl ketone, methyl isobutyl ketone,tetrahydrofuran, dichloromethane, 1,2-dichloroethane, benzene, toluene,dimethylformamide and the like are preferable.

As bases usable in the present reaction, those exemplified in theexplanation of the PROCESS A-2 can be exemplified.

In the present reaction, 0.5 to 2 moles of the compound having theformula (VIII) is used per mole of the compound having the formula(VII).

The base is used in an amount of at least equivalent mole, generally 1to 5 moles per mole of the compound having the formula (VII).

The reaction temperature can be suitably selected in the range of fromroom temperature to the boiling point of the used solvent. The reactiontime can be suitably selected in the range of from 0.5 to 100 hours.

PROCESS B

The desired compound having the formula (III) can be prepared byreducing the compound having the formula (II) in an inactive solvent.

In the present reaction, although any common means for reduction ofnitro group into amino group can be used, the reaction are preferablycarried out with a metal such as tin, zinc or iron at the pH of fromneutral to weak acid. For example, a process using the combination ofzinc and calcium chloride or the combination of iron and acetic acid canbe exemplified.

The inactive solvents usable in the present reaction are notparticularly limited, if the solvents do not considerably inhibit thistype of reaction. As such solvents, for example, water, methyl alcohol,ethyl alcohol, propyl alcohol, tetrahydrofuran, dioxane, an aqueousmixture thereof and the like are preferable.

The reaction temperature can be suitably selected in the range of fromroom temperature to the boiling point of the used solvent. The reactiontime can be suitably selected in the range of from 0.5 to 10 hours.

PROCESS C

The desired compound having the formula (Ia) can be prepared by reactingthe compound having the formula (III) and the compound having theformula (IX) in the presence of a base in an inactive solvent.

The inactive solvents usable in the present reaction are notparticularly limited, if the solvents do not considerably inhibit thistype of reaction. As such solvents, for example, acetone, methyl ethylketone, tetrahydrofuran, dichloromethane, chloroform,1,2-dichloroethane, benzene, pyridine and the like are preferable.

Bases usable in the present reaction are not particularly limited, ifthey usually act as bases. As such bases, for example, organic bases oftertiary amine such as triethylamine and pyridine are preferable.

In the present reaction, 1 to 1.5 moles of the compound having theformula (IX) is used per mole of the compound having the formula (III).

The base is used in an amount of at least equivalent mole per mole ofthe compound having the formula (III).

The reaction is usually carried out under cooling or at roomtemperature. The reaction time can be suitably selected in the range offrom a few minutes to 10 hours.

PROCESS D

The desired compound having the formula (Ib) can be prepared by reactingthe compound having the formula (Ia) and the compound having the formula(X) in the presence of a base in an inactive solvent.

The inactive solvents usable in the present reaction are notparticularly limited, if the solvents do not considerably inhibit thistype of reaction. As such solvents, for example, methyl alcohol, ethylalcohol, propyl alcohol, tetrahydrofuran, dimethylformamide and the likeare preferable.

As bases usable in the present reaction, for example, inorganic basessuch as sodium hydride, sodium amide and an alcoholate of alkaline metalsuch as sodium or potassium are preferable.

In the present reaction, 1 to 2 moles of the compound having the formula(X) is used per mole of the compound having the formula (Ia).

The base is used in an amount of 1 to 1.5 moles per mole of the compoundhaving the formula (Ia).

The reaction temperature can be suitably selected in the range of from0° C. to the boiling point of the used solvent. The reaction time can besuitably selected in the range of from 0.5 to 10 hours.

The desired compounds prepared according to the above-mentionedprocesses A-1-D can be isolated and purified by a usual method.

The desired compounds prepared according to the process A-2, A-3, B andC may be obtained in the form of salts with hydrohalogenic acid such ashydrochloric acid, hydrobromic acid or hydroiodic acid, depending uponthe kinds of the reactants, reaction conditions or the conditions of theisolation or purification.

In the above-mentioned case, an inorganic base such as sodium carbonate,potassium carbonate, sodium hydroxide or potassium hydroxide or anaqueous solution thereof may be added to carry out dehydrohalogenation,thereby a desired free compound being obtained.

Thus obtained piperidine derivative having the formula (I) has both ofthe inhibition activity of mediator release in allergic reaction andantihistaminic activity. Therefore the piperidine derivative of thepresent invention having the formula (I) has an excellent anti-allergicactivity and so shows excellent effects for prevention and treatment ofvarious allergic diseases such as allergic asthma, allergic dermatitis,allergic rhinitis, allergic gastroenteritis, vernal conjunctivitis andallergic conjunctivitis.

Furthermore, the piperidince derivative of the present invention havingthe formula (I) has also excellent therapeutic activity for ischemicheart disease such as stenocardia and myocardial infarction.

The piperidine derivative of the present invention having the formula(I) can be used as it is or in various pharmaceutical preparation formsaccording to known pharmaceutical preparation process. The piperidinederivative of the present invention having the formula (I) can be usedin pharmaceutical preparations for oral administration such as tablets,capsules, granule, powder and syrup or pharmaceutical preparations forparenteral administration such as injection, collunarium, eye drops,ointment and suppository.

Although the dosage of the compound of the present invention having theformula (I) is different according to the sympton, age or body weight ofa patient, treatment effect, or method or period of administration, asuitable dosage is generally 0.1 to 200 mg in case of oraladministration on the basis of the compound (I) of the present inventionper day for adults.

The piperidine derivative having the formula (II) or (III) is useful asan intermediate for preparing the compound having the formula (I) andhas also excellent therapeutic activity for ischemic heart disease suchas stenocardia and myocardial infarction.

The present invention is more specifically described and explained bymeans of the following Examples. It is to be understood that the presentinvention is not limited to the Examples, and various changes andmodifications may be made in the invention without departing from thespirit and scope thereof.

EXAMPLE 1 Preparation of4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR85##

(a) Into 270 ml of methyl isobutyl ketone were dissolved 32.1 g ofdiphenylmethyl bromide, 28.0 g of4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine and 30.4 g oftriethylamine. The resultant solution was heated under reflux withstirring for 15 hours. After cooling, the reaction solution was washedwith water, and the solvent was removed under reduced pressure. Theresidue was eluted with methanol-chloroform (1:50) by silica gel columnchromatography to give 33.9 g of oily4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.63-2.21 (8H,m), 2.51 (2H,t), 2.77 (2H,m), 3.43(1H,m), 4.15 (2H,t), 5.52 (1H,s), 6.95-7.54 (13H,m), 7.81 (1H,d)

(b) A mixture of 20.0 g of the nitro compound obtained in (a), 58.0 g ofzinc powder, 9.0 g of calcium chloride, 600 ml of ethanol and 160 ml ofwater was heated under reflux with stirring for 2 hours. The reactionmixture was filtered, and the filtrate was concentrated. Water was addedto the concentrate, and the mixture was extracted with ethyl acetate.The resultant organic layer was washed with water, and the solvent wasremoved under reduced pressure to give 16.1 g of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine. m.p.: 86°-88°C. (recrystallized from n-hexane)

¹ H-NMR (CDCl₃) δ:1.63-2.07 (6H,m), 2.13 (2H,br t), 2.50 (2H,t), 2.77(2H,m), 3.44 (1H,m), 3.83 (2H,br s), 4.02 (2H,t), 5.52 (1H,s), 6.62-6.83(4H,m), 7.18-7.42 (10H,m)

(c) Into 25 ml of pyridine was dissolved 2.5 g of the amino compoundobtained in (b). To the resultant solution was added dropwise 0.83 g ofmethanesulfonyl chloride at room temperature, and the mixture wasstirred for 1 hour. The reaction solution was poured into ice water, andextracted with ethyl acetate. The extract was washed with water, andethyl acetate was removed. The residue was eluted withmethanol-chloroform (1:50) by silica gel column chromatography to give2.1 g of the desired compound.

m.p.: 106°-107° C. (recrystallized from ethanol)

¹ H-NMR (CDCl₃) δ:1.66-1.82 (2H,m), 1.84-2.04 (4H,m), 2.17 (2H,br t),2.48 (2H,t), 2.76 (2H,m), 2.94 (3H,s), 3.46 (1H,m), 4.08 (2H,t), 5.52(1H,s), 6.89-7.55 (14H,m)

EXAMPLE 2 Preparation of4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidinehydrochloride.

Into 20 ml of ethanol was dissolved 0.50 g of4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidineobtained in Example 1 (c), and 0.13 ml of 36% HCl was added dropwise tothe resultant solution with cooling and stirring. The mixture was driedunder reduced pressure to form a solid. The residue was recrystallizedfrom isopropyl alcohol to give 0.43 g of the desired compound.

m.p.: 180°-182° C.

EXAMPLE 3 Preparation of4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidinefumarate

Into 40 ml of ethanol were dissolved at first 1.0 g of4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]-piperidineobtained in Example 1 (c) and then 0.234 g of fumaric acid. The mixturewas dried under reduced pressure to form a solid. The residue wasrecrystallized from isopropyl alcohol to give 0.98 g of the desiredcompound.

m.p.: 179.5°-181° C.

EXAMPLE 4 Preparation of4-diphenylmethoxy-1-[3-(2-ethanesulfonylaminophenoxy)propyl]piperidine##STR86##

The procedure of Example 1 (c) was repeated except for using4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine obtained inExample 1 (b) and ethanesulfonyl chloride instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine andmethanesulfonyl chloride to give the desired compound.

¹ H-NMR (CDCl₃) δ:1.32 (3H,t), 1.67-1.82 (2H,m), 1.83-2.04 (4H,m),2.07-2.26 (2H,m), 2.47 (2H,t), 2.75 (2H,m), 3.06 (2H,q), 3.46 (1H,m),4.08 (2H,t), 5.52 (1H,s), 6.88-7.58 (14H,m)

EXAMPLE 5 Preparation of4-diphenylmethoxy-1-[3-[2-(2-thiophene)sulfonylaminophenoxy]propyl]piperidine##STR87##

The procedure of Example 1 (c) was repeated except for using4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine obtained inExample 1 (b) and 2-thiophenesulfonyl chloride instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine andmethanesulfonyl chloride to give the desired compound.

m.p.: 119°-120° C. (recrystallized from ethanol)

¹ H-NMR (CDCl₃) δ:1.68-1.98 (6H,m), 2.26 (2H,m), 2.43 (2H,t), 2.76(2H,m), 3.48 (1H,m), 3.86 (2H,t), 5.52 (1H,s), 6.76-7.63 (17H,m)

EXAMPLE 6 Preparation of4-diphenylmethoxy-1-[3-(2-benzenesulfonylaminophenoxy)propyl]piperidine##STR88##

Into 25 ml of pyridine was dissolved 1.0 g of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine obtained inExample 1 (b), and 0.51 g of benzenesulfonyl chloride was added dropwiseto the resultant solution at room temperature, followed by stirring for30 minutes. The reaction solution was poured into ice water, andextracted with chloroform. The extract was washed with water, andchloroform was removed. The residue was eluted with ethylacetate-chloroform (1:1) by silica gel column chromatography to give0.79 g of the desired compound.

m.p.: 131°-132° C.

¹ H-NMR (CDCl₃) δ:1.66-1.98 (6H,m), 2.15 (2H,br t), 2.35 (2H,t), 2.73(2H,m), 3.46 (1H,m), 3.78 (2H,t), 5.53 (1H,s), 6.70-7.77 (19H,m)

EXAMPLE 7 Preparation of4-diphenylmethoxy-1-[3-(2-trifluoromethanesulfonylaminophenoxy)propyl]piperidine##STR89##

Into 25 ml of dichloromethane were dissolved 1.0 g of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine obtained inExample 1 (b) and 0.32 g of triethylamine, and 0.71 g oftrifluoromethanesulfonic anhydride was added dropwise to the resultantsolution at -78° C., followed by stirring for 1 hour. The reactionsolution was washed with water, and the solvent was removed underreduced pressure. The residue was recrystallized fromdichloromethane-ethyl acetate to give 0.98 g of the desired compound.

m.p.: >190° C.

¹ H-NMR (CDCl₃) δ:1.89-2.20 (6H,m), 3.16 (2H,m), 3.29 (2H,t), 3.75 (3H,br s), 4.11 (2H,t), 5.42 (1H,s), 6.78-7.04 (3H,m), 7.18-7.38 (10H,m),7.57 (1H,dd)

EXAMPLE 8 Preparation of4-diphenylmethoxy-1-[3-(2-N-methyl-N-methanesulfonylaminophenoxy)propyl]piperidine##STR90##

Into 20 ml of N,N-dimethylformamide was dissolved 1.0 g of4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidineobtained in Example 1 (c), and 0.14 g of sodium hydride (60%, in oil)was added to the resultant solution with ice cooling, followed bystirring for 30 minutes. Then 0.40 g of methyl iodide was added dropwiseto the mixture, and the mixture was stirred at room temperature for 1hour. The reaction solution was poured into ice water, and extractedwith ethyl acetate. The extract was washed with water, and the solventwas removed. The residue was eluted with ethyl acetate by silica gelcolumn chromatography to give 0.81 g of the desired compound.

¹ H-NMR (CDCl₃) δ:1.68-1.84 (2H,m), 1.87-2.09 (4H,m), 2.20 (2H,m), 2.53(2H,t), 2.78 (2H,m), 2.92 (3H,s), 3.25 (3H,s), 3.47 (1H,m), 4.08 (2H,t),5.52 (1H,s), 6.91-7.00 (2H,m), 7.20-7.41 (12H,m)

EXAMPLE 9 Preparation of4-diphenylmethoxy-1-[2-(2-methanesulfonylaminophenoxy)ethyl]piperidine##STR91##

(a) The procedure of Example 1 (a) was repeated except for usingdiphenylmethyl bromide and4-hydroxy-1-[2-(2-nitrophenoxy)ethyl]piperidine instead ofdiphenylmethyl bromide and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-diphenylmethoxy-1-[2-(2-nitrophenoxy)ethyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.65-1.80 (2H,m), 1.83-1.97 (2H,m), 2.31 (2H,m),2.78-2.93 (4H,m), 3.44 (1H,m), 4.21 (2H,t), 5.52 (1H,s), 6.96-7.53(13H,m), 7.81 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[2-(2-aminophenoxy)ethyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.70-2.02 (4H,m), 2.47 (2H,m), 2.70-2.92 (4H,m), 3.15(3H,s), 3.53 (1H,m), 4.18 (2H,t), 5.48 (1H,s), 6.93-7.05 (2H,m),7.18-7.44 (12H,m)

EXAMPLE 10 Preparation of4-diphenylmethoxy-1-[3-(3-methanesulfonylaminophenoxy)propyl]piperidine##STR92##

(a) The procedure of Example 1 (a) was repeated except for usingdiphenylmethyl bromide and4-hydroxy-1-[3-(3-nitrophenoxy)propyl]piperidine instead ofdiphenylmethyl bromide and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-diphenylmethoxy-1-[3-(3-nitrophenoxy)propyl]piperidine.

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[3-(3-aminophenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

m.p.: 90°-95.5° C.

¹ H-NMR (CDCl₃) δ:1.90-2.06 (2H,m), 2.16-2.37 (4H,m), 2.97 (3H,s),2.93-3.21 (6H,m), 3.73 (1H,m), 3.98 (2H,t), 5.45 (1H,s), 6.61 (1H,d),6.88-6.98 (2H,m) 7.11-7.39 (11H,m)

EXAMPLE 11 Preparation of4-diphenylmethoxy-1-[3-(4-methanesulfonylaminophenoxy)propyl]piperidine##STR93##

(a) The procedure of Example 1 (a) was repeated except for usingdiphenylmethyl bromide and4-hydroxy-1-[3-(4-nitrophenoxy)propyl]piperidine instead ofdiphenylmethyl bromide and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-diphenylmethoxy-1-[3-(4-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.64-1.81 (2H,m), 1.82-2.04 (4H,m), 2.15 (2H,br t),2.48 (2H,t), 2.75 (2H,m), 3.45 (1H,m), 4.09 (2H,t), 5.52 (1H,s), 6.93(2H,d), 7.19-7.40 (10H,m), 8.17 (2H,d)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[3-(4-aminophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.63-1.80 (2H,m), 1.82-1.98 (4H,m), 2.13 (2H,br t),2.46 (2H,t), 2.76 (2H,m), 3.26-3.50 (3H,m), 3.91 (2H,t), 5.51 (1H,s),6.61 (2H,d), 6.72 (2H,d), 7.19-7.40 (10H,m)

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

m.p.: 41°-43° C.

¹ H-NMR (CDCl₃) δ:1.70-1.86 (2H,m), 1.88-2.07 (4H,m), 2.30 (2H,m), 2.56(2H,t), 2.81 (2H,m), 2.92 (3H,s), 3.49 (1H,m), 3.97 (2H,t), 5.51 (1H,s),6.85 (2H,d), 7.15-7.43 (12H,m)

EXAMPLE 12 Preparation of4-diphenylmethoxy-1-[3-(5-fluoro-2-methanesulfonylaminophenoxy)propyl]piperidine##STR94##

(a) The procedure of Example 1 (a) was repeated except for usingdiphenylmethyl bromide and4-hydroxy-1-[3-(5-fluoro-2-nitrophenoxy)propyl]piperidine instead ofdiphenylmethyl bromide and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-diphenylmethoxy1-[3-(5-fluoro-2-nitrophenoxy)propyl]piperidine.

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[3-(2-amino-5-fluorophenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

m.p.: 52°-56° C.

¹ H-NMR (CDCl₃) δ:1.64-2.05 (6H,m), 2.17 (2H,m), 2.48 (2H,t), 2.75(2H,m), 2.85 (3H,s), 3.62 (1H,m), 4.03 (2H,t), 5.51 (1H,s), 6.44-6.53(2H,m), 7.20-7.41 (11H,m)

EXAMPLE 13 Preparation of4-diphenylmethoxy-1-[3-(2-methanesulfonylamino-3-methylphenoxy)propyl]piperidine##STR95##

(a) The procedure of Example 1 (a) was repeated except for usingdiphenylmethyl bromide and4-hydroxy-1-[3-(3-methyl-2-nitrophenoxy)propyl]piperidine instead ofdiphenylmethyl bromide and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-diphenylmethoxy-1-[3-(3-methyl-2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.72-1.88 (2H,m), 1.95-2.13 (4H,m), 2.29 (3H,s), 2.45(2H,m), 2.63 (2H,br t), 2.88 (2H,m), 3.55 (1H,m), 4.12 (2H,t), 5.49(1H,s), 6.79-6.89 (2H,m), 7.17-7.37 (11H,m)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[3-(2-amino-3-methylphenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

m.p.: 131.5°-132.5° C. (recrystallized from dichloromethane-n-hexane)

¹ H-NMR (CDCl₃) δ:1.64-1.80 (2H,m), 1.82-2.01 (4H,m), 2.16 (2H,br t),2.40-2.50 (5H,m), 2.73 (2H,m), 2.94 (3H,s), 3.46 (1H,m), 4.07 (2H,t),5.52 (1H,s), 6.74-6.91 (2H,m), 7.10-7.38 (11H,m)

EXAMPLE 14 Preparation of4-diphenylmethoxy-1-[3-(2-methanesulfonylamino-4-methylphenoxy)propyl]piperidine##STR96##

(a) The procedure of Example 1 (a) was repeated except for usingdiphenylmethyl bromide and4-hydroxy-1-[3-(4-methyl-2-nitrophenoxy)propyl]piperidine instead ofdiphenylmethyl bromide and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-diphenylmethoxy-1-[3-(4-methyl-2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.65-1.82 (2H,m), 1.86-2.09 (4H,m), 2.23 (2H,m), 2.33(3H,s), 2.57 (2H,br t), 2.81 (2H,m), 3.47 (1H,m), 4.13 (2H,t), 5.51(1H,s), 6.93-7.65 (13H,m)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[3-(2-amino-4-methylphenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.65-1.81 (2H,m), 1.83-2.01 (4H,m), 2.16 (2H,br t),2.29 (3H,s), 2.47 (2H, t), 2.76 (2H,m), 2.93 (3H,s), 3.46 (1H,m), 4.04(2H,t), 5.52 (1H,s), 6.76-6.93 (2H,m), 7.12-7.38 (11H,m)

EXAMPLE 15 Preparation of4-diphenylmethoxy-1-[3-(2-methanesulfonylamino-5-methylphenoxy)propyl]piperidine##STR97##

(a) The procedure of Example 1 (a) was repeated except for usingdiphenylmethyl bromide and4-hydroxy-1-[3-(5-methyl-2-nitrophenoxy)propyl]piperidine instead ofdiphenylmethyl bromide and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-diphenylmethoxy-1-[3-(5-methyl-2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.80-1.96 (2H,m), 2.08-2.33 (4H,m), 2.40 (3H,s), 2.75(2H,m), 2.89 (2H,br t), 3.02 (2H,m), 3.65 (1H,m), 4.19 (2H,t), 5.48(1H,s), 6.78-6.89 (2H,m), 7.20-7.38 (10H,m) 7.79 (1H,d)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[3-(2-amino-5-methylphenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.65-1.81 (2H,m), 1.83-2.02 (4H,m), 2.17 (2H,br t),2.32 (3H,s), 2.47 (2H,t), 2.76 (2H,m), 2.90 (3H,s), 3.46 (1H,m), 4.06(2H,t), 5.52 (1H,s), 6.71-6.79 (2H,m), 7.18-7.40 (11H,m)

EXAMPLE 16 Preparation of4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)-1-methylpropyl]piperidine##STR98##

(a) The procedure of Example 1 (a) was repeated except for usingdiphenylmethyl bromide and4-hydroxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine instead ofdiphenylmethyl bromide and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-diphenylmethoxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:0.96 (3H,d), 1.50-2.02 (6H,m), 2.12 (1H,m), 2.35(1H,m), 2.59-2.80 (2H,m), 2.81-2.96 (1H,m), 3.37 (1H,m), 4.07-4.27(2H,m), 5.52 (1H,s), 6.92-7.53 (13H,m), 7.80 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[3-(2-aminophenoxy)-1-methylpropyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

m.p.: 114°-115.5° C. (recrystallized from ethanol)

¹ H-NMR (CDCl₃) δ:0.98 (3H,d), 1.55-2.00 (6H,m), 2.17 (1H,br t), 2.40(1H,br t), 2.67 (1H, m), 2.72-2.88 (2H,m), 2.93 (3H,s), 3.40 (1H,m),4.00-4.18 (2H,m), 5.52 (1H,s), 6.88-7.54 (14H,m)

EXAMPLE 17 Preparation of4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)-2-methylpropyl]piperidine##STR99##

(a) The procedure of Example 1 (a) was repeated except for usingdiphenylmethyl bromide and4-hydroxy-1-[2-methyl-3-(2-nitrophenoxy)propyl]piperidine instead ofdiphenylmethyl bromide and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-diphenylmethoxy-1-[2-methyl-3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.04 (3H,d), 1.57-1.77 (2H,m), 1.79-2.45 (7H,m), 2.66(1H,m), 2.78 (1H,m), 3.40 (1H,m), 3.85-3.98 (1H,m), 4.05-4.16 (1H,m),5.51 (1H,s), 6.89-7.52 (13H,m), 7.79 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[3-(2-aminophenoxy)-2-methylpropyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.00 (3H,d), 1.60-1.79 (2H,m), 1.86 (2H,m), 1.98-2.41(5H,m), 2.67 (1H,m), 2.77 (1H,m), 2.85 (3H,s), 3.42 (1H,m), 3.76-3.87(1H,m), 3.93-4.05 (1H,m), 5.50 (1H,s) 6.85-7.52 (14H,m)

EXAMPLE 18 Preparation of4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)-3-methylpropyl]piperidine##STR100##

(a) The procedure of Example 1 (a) was repeated except for usingdiphenylmethyl bromide and4-hydroxy-1-[3-methyl-3-(2-nitrophenoxy)propyl]piperidine instead ofdiphenylmethyl bromide and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-diphenylmethoxy1-[3-methyl-3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.35 (3H,d), 1.57-2.20 (8H,m), 2.46 (2H,m), 2.62-2.82(2H,m), 3.43 (1H,m), 4.64 (1H,m), 5.51 (1H,s), 6.91-7.50 (13H,m), 7.75(1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[3-(2-aminophenoxy)-3-methylpropyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.30 (3H,d), 1.62-1.81 (2H,m), 1.82-1.97 (4H,m),2.07-2.28 (2H,m), 2.32-2.55 (2H,m), 2.75 (2H,m), 2.94 (3H,s), 3.46(1H,m), 4.50 (1H,m), 5.51 (1H,s), 6.89-7.53 (14H,m)

EXAMPLE 19 Preparation of4-diphenylmethoxy-1-[4-(2-methanesulfonylaminophenoxy)butyl]piperidine##STR101##

(a) The procedure of Example 1 (a) was repeated except for usingdiphenylmethylbromide and4-hydroxy-1-[4-(2-nitrophenoxy)butyl]piperidine instead ofdiphenylmethyl bromide and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-diphenylmethoxy-1-[4-(2-nitrophenoxy)butyl]piperidine.

¹ H-NMR (CDCl₃)δ: 1.58-1.97 (8H,m), 2.10 (2H,br t), 2.36 (2H,t), 2.75(2H,m), 3.43 (1H,m), 4.11 (2H,t), 5.52 (1H,s), 6.93-7.55 (13H,m), 7.81(1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[4-(2-aminophenoxy)butyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃)δ: 1.58-2.00 (8H,m), 2.22 (2H,m), 2.42 (2H,br t), 2.77(2H,m), 2.95 (3H,s), 3.47 (1H,m), 4.05 (2H,t), 5.51 (1H,s), 6.85-7.55(14H,m)

EXAMPLE 20 Preparation of4-diphenylmethoxy-1-[4-(2-methanesulfonylaminophenoxy)-2(E)-butenyl]piperidine##STR102##

(a) Into 35 ml of dichloromethane were dissolved 2.67 g of4-diphenylmethoxypiperidine, 2.96 g of1-chloro-4-(2-nitrophenoxy)-2(E)-butene and 1.68 g ofN,N-diisopropylethylamine, and the resultant solution was stirred atroom temperature for 48 hours. The reaction solution was washed withwater, and the solvent was removed under reduced pressure. The residuewas eluted with ethanol-ethyl acetate (1:5) by silica gel columnchromatography to give 2.75 g of oily4-diphenylmethoxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine.

¹ H-NMR (CDCl₃)δ: 1.64-1.97 (4H,m), 2.05-2.25 (2H,m), 2.64-2.81 (2H,m),3.01 (2H,br d), 3.45 (1H,m), 4.66 (2H,br d), 5.51 (1H,s), 5.75-6.00(2H,m), 6.94-7.52 (13H,m), 7.81 (1H,d)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[4-(2-aminophenoxy)-2(E)-butenyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃)δ: 1.65-1.98 (4H,m), 2.08-2.29 (2H,m), 2.73 (2H,m), 2.94(3H,s), 3.02 (2H,br d), 3.47 (1H,m), 4.57 (2H,br d), 5.51 (1H,s),5.74-5.92 (2H,m), 6.88-7.58 (14H,m)

EXAMPLE 21 Preparation of4-diphenylmethoxy-1-[4-(2-methanesulfonylaminophenoxy)-2(Z)-butenyl]piperidine##STR103##

(a) The procedure of Example 20 (a) was repeated except for using4-diphenylmethoxypiperidine and 1-chloro-4-(2-nitrophenoxy)-2(Z)-buteneinstead of 4-diphenylmethoxypiperidine and1-chloro-4-(2-nitrophenoxy)-2(E)-butene to give oily4-diphenylmethoxy-1-[4-(2-nitrophenoxy)-2(Z)-butenyl]piperidine.

¹ H-NMR (CDCl₃)δ: 1.64-1.97 (4H,m), 2.05-2.25 (2H,m), 2.64-2.81 (2H,m),3.06 (2H,br d), 3.45 (1H,m), 4.75 (2H,br d), 5.51 (1H,s), 5.70-5.87(2H,m), 6.94-7.52 (13H,m), 7.81 (1H,d)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[4-(2-aminophenoxy)-2(Z)-butenyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃)δ: 1.65-1.98 (4H,m), 2.08-2.29 (2H,m), 2.73 (2H,m), 2.93(3H,s), 3.04 (2H,br d), 3.47 (1H,m), 4.66 (2H,br d), 5.51 (1H,s),5.74-5.92 (2H,m), 6.88-7.58 (14H,m)

EXAMPLE 22 Preparation of4-diphenylmethoxy-1-[4-(2-methanesulfonylaminophenoxy)-2-butynyl]piperidin##STR104##

(a) Into 35 ml of dichloromethane were dissolved 2.67 g of4-diphenylmethoxypiperidine, 2.93 g of1-chloro-4-(2-nitrophenoxy)-2-butyne and 1.68 g ofN,N-diisopropylethylamine, and the resultant solution was stirred atroom temperature for 20 hours. The reaction solution was washed withwater, and the solvent was removed under reduced pressure. The residuewas eluted with ethyl acetate by silica gel column chromatography togive 2.95 g of oily4-diphenylmethoxy-1-[4-(2-nitrophenoxy)-2-butynyl]piperidine.

¹ H-NMR (CDCl₃)δ: 1.62-1.94 (4H,m), 2.21 (2H,m), 2.70 (2H,m), 3.29(2H,s), 3.37 (1H,m), 4.85 (2H,s), 5.51 (1H,s), 6.92-7.44 (13H,m), 7.77(1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[4-(2-nitrophenoxy)-2-butynyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃)δ: 1.65-1.95 (4H,m), 2.10-2.28 (2H,m), 2.63-2.76 (2H,m),2.92 (3H,s), 3.29 (2H,s), 3.37 (1H,m), 4.77 (2H,s), 5.51 (1H,s),6.75-7.54 (14H,m)

EXAMPLE 23 Preparation of4-diphenylmethoxy-1-[5-(2-methanesulfonylaminophenoxy)pentyl]piperidine##STR105##

(a) The procedure of Example 1 (a) was repeated except for usingdiphenylmethyl bromide and4-hydroxy-1-[5-(2-nitrophenoxy)pentyl]piperidine instead ofdiphenylmethyl bromide and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-diphenylmethoxy-1-[5-(2-nitrophenoxy)pentyl]piperidine.

¹ H-NMR (CDCl₃)δ: 1.40-1.64 (4H,m), 1.66-1.99 (6H,m), 2.18 (2H,m), 2.36(2H,br t), 2.77 (2H,m), 3.46 (1H,m), 4.08 (2H,t), 5.51 (1H,s), 6.94-7.54(13H,m), 7.80 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-diphenylmethoxy-1-[5-(2-aminophenoxy)pentyl]piperidine.

m.p.: 80°-81° C. (recrystallized from n-hexane)

¹ H-NMR (CDCl₃)δ: 1.39-1.62 (4H,m), 1.65-1.95 (6H,m), 2.10 (2H,m), 2.32(2H,t), 2.74 (2H,m), 3.43 (1H,m), 3.77 (2H,br s), 3.97 (2H,t), 5.52(1H,s) 6.66-6.82 (4H,m), 7.19-7.39 (10H,m)

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃)δ: 1.38-1.65 (4H,m), 1.66-1.98 (6H,m), 2.17 (2H,m), 2.35(2H,t), 2.76 (2H,m), 2.94 (3H,s), 3.46 (1H,m), 4.02 (2H,t), 5.51 (1H,s),6.84-7.54 (14H,m)

EXAMPLE 24 Preparation of4-[(2-chlorophenyl)-phenylmethoxy]-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR106##

(a) Into 50 ml of toluene were dissolved 3.02 g of4-[(2-chlorophenyl)-phenylmethoxy]piperidine, 2.59 g of1-chloro-3-(2-nitrophenoxy)propane and 3.04 g of triethylamine, and theresultant solution was heated under reflux with stirring for 15 hours.After cooling, the reaction solution was washed with water, and thesolvent was removed under reduced pressure. The residue was eluted withmethanol-chloroform (1:50) by silica gel column chromatography to give3.55 g of oily4-[(2-chlorophenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃)δ: 1.61-1.80 (2H,m), 1.82-2.25 (6H,m), 2.52 (2H,t),2.69-2.84 (2H,m), 3.43 (1H,m), 4.15 (2H,t), 5.98 (1H,s), 6.94-7.63(12H,m), 7.81 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-[(2-chlorophenyl)-phenylmethoxy]-1-[3-(2-aminophenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃)δ: 1.72-1.89 (2H,m), 1.93-2.15 (4H,m), 2.42 (2H,m), 2.64(2H,br t), 2.78-2.92 (2H,m), 2.96 (3H,s), 3.52 (1H,m), 4.09 (2H,t), 5.97(1H,s), 6.87-7.60 (13H,m)

EXAMPLE 25 Preparation of4-[(4-chlorophenyl)-phenylmethoxy]-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine.##STR107##

(a) The procedure of Example 24 (a) was repeated except for using4-[(4-chlorophenyl)-phenylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane instead of4-[(2-chlorophenyl)-phenylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane to give oily4-[(4-chlorophenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃)δ: 1.60-1.77 (2H,m), 1.86 (2H,m), 1.98 (2H,quint), 2.13(2H,br t), 2.51 (2H,t), 2.76 (2H,m), 3.41 (1H,m), 4.15 (2H,t), 5.48(1H,s) 6.94-7.53 (12H,m), 7.80 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-[(4-chlorophenyl)-phenylmethoxy]-1-[3-(2-aminophenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃)δ: 1.63-1.79 (2H,m), 1.81-2.02 (4H,m), 2.16 (2H,br t),2.47 (2H,t), 2.75 (2H,m), 2.94 (3H,s), 3.43 (1H,m), 4.08 (2H,t), 5.48(1H,s) 6.89-7.37 (12H,m), 7.52 (1H,dd)

EXAMPLE 26 Preparation of4-[(2-methylphenyl)-phenylmethoxy]-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR108##

(a) The procedure of Example 24 (a) was repeated except for using4-[(2-methylphenyl)-phenylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane instead of4-[(2-chlorophenyl)-phenylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane to give oily4-[(2-methylphenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.58-2.20 (8H,m), 2.25 (3H,s), 2.50 (2H,t), 2.77(2H,m), 3.41 (1H,m), 4.15 (2H,t), 5.69 (1H,s), 6.93-7.57 (12H,m), 7.81(1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-[(2-methylphenyl)-phenylmethoxy]-1-[3-(2-aminophenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.61-1.81 (2H,m), 1.83-2.02 (4H,m), 2.04-2.22 (2H,m),2.25 (3H,s), 2.48 (2H,t), 2.77 (2H,m), 2.94 (3H,s), 3.44 (1H,m), 4.08(2H,t), 5.69 (1H,s), 6.88-7.55 (13H,m)

EXAMPLE 27 Preparation of4-[(3-methylphenyl)-phenylmethoxy]-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR109##

(a) The procedure of Example 24 (a) was repeated except for using4-[(3-methylphenyl)-phenylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane instead of4-[(2-chlorophenyl)-phenylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane to give oily4-[(3-methylphenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.63-1.80 (2H,m), 1.83-2.07 (4H,m), 2.17 (2H,m), 2.32(3H,s), 2.54 (2H,t), 2.79 (2H,m), 3.44 (1H,m), 4.16 (2H,t), 5.48 (1H,s),6.95-7.54 (12H,m), 7.81 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-[(3-methylphenyl)-phenylmethoxy]-1-[3-(2-aminophenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.65-1.81 (2H,m), 1.83-2.03 (4H,m), 2.16 (2H,br t),2.32 (3H,s), 2.48 (2H,t), 2.76 (2H,m), 2.94 (3H,s), 3.45 (1H,m), 4.08(2H,t), 5.48 (1H,s), 6.90-7.38 (12H, m), 7.51 (1H,d)

EXAMPLE 28 Preparation of4-[(4-methylphenyl)-phenylmethoxy]-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR110##

(a) The procedure of Example 24 (a) was repeated except for using4-[(4-methylphenyl)-phenylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane instead of4-[(2-chlorophenyl)-phenylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane to give oily4-[(4-methylphenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-[(4-methylphenyl)-phenylmethoxy]-1-[3-(2-aminophenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.64-1.79 (2H,m), 1.80-2.03 (4H,m), 2.17 (2H,br t),2.32 (3H,s), 2.48 (2H,t), 2.76 (2H,m), 2.94 (3H,s), 3.45 (1H,m), 4.08(2H,t), 5.49 (1H,s), 6.88-7.54 (13H,m),

EXAMPLE 29 Preparation of4-[(4-methoxyphenyl)-phenylmethoxy]-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR111##

(a) The procedure of Example 24 (a) was repeated except for using4-[(4-methoxyphenyl)-phenylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane instead of4-[(2-chlorophenyl)-phenylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane to give oily4-[(4-methoxyphenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.58-1.78 (2H,m), 1.86 (2H,m), 1.98 (2H,quint), 2.12(2H,br t), 2.50 (2H,t), 2.76 (2H,m), 3.41 (1H,m), 3.78 (3H,s), 4.15(2H,t), 5.48 (1H,s), 6.80-7.54 (12H,m), 7.81 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-[(4-methoxyphenyl)-phenylmethoxy]-1-[3-(2-aminophenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.63-1.80 (2H,m), 1.82-2.03 (4H,m), 2.16 (2H,br t),2.48 (2H,t), 2.76 (2H,m), 2.94 (3H,s), 3.44 (1H,m), 3.78 (3H,s), 4.08(2H,t), 5.48 (1H,s), 6.79-7.38 (12H,m), 7.52 (1H,d)

EXAMPLE 30 Preparation of4-di(4-fluorophenyl)methoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR112##

(a) The procedure of Example 1 (a) was repeated except for usingdi(4-fluorophenyl)methyl chloride and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine instead ofdiphenylmethyl bromide and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-di(4-fluorophenyl)methoxy-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.54-1.77 (2H,m), 1.80-1.94(2H,m), 1.99 (2H,quint),2.12 (2H,m), 2.52 (2H,t), 2.75 (2H,m), 3.38 (1H,m), 4.15 (2H,t), 5.47(1H,s), 6.90-7.14 (6H,m), 7.20-7.35 (4H,m), 7.50 (1H,t), 7.82 (1H,d)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-di(4-fluorophenyl)methoxy-1-[3-(2-aminophenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.62-1.79 (2H,m), 1.82-2.03 (4H,m), 2.16 (2H,br t),2.48 (2H,t), 2.75 (2H,m), 2.94 (3H,s), 3.42 (1H,m), 4.08 (2H,t), 5.47(1H,s), 6.89-7.33 (11H,m), 7.52 (1H,d),

EXAMPLE 31 Preparation of4-(cyclopentyl-phenylmethoxy)-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR113##

(a) Into 35 ml of methyl isobutyl ketone were dissolved 2.92 g ofcyclopentyl-phenylmethyl chloride, 2.80 g of4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine and 1.94 g ofN,N-diisopropylethylamine, and the resultant solution was heated underreflux with stirring for 72 hours. After cooling, the reaction solutionwas washed with water, and the solvent was removed under reducedpressure. The residue was eluted with ethylacetate-ethanol-dichloromethane (1:1:1) by silica gel columnchromatography to give 0.88 g of oily4-(cyclopentyl-phenylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.00-1.72 (11H,m), 1.78-2.20 (6H,m), 2.50 (2H,t),2.60-2.80 (2H,m), 3.19 (1H,m), 4.05 (1H,d), 4.15 (2H,t), 6.95-7.56(8H,m), 7.81 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-(cyclopentyl-phenylmethoxy)-1-[3-(2-aminophenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.03-1.74 (11H,m), 1.78-2.26 (6H,m), 2.47 (2H,t),2.59-2.80 (2H,m), 2.94 (3H,s), 3.21 (1H,m), 3.98-4.13 (3H,m), 6.88-7.37(8H,m) 7.51 (1H, dd)

EXAMPLE 32 Preparation of4-(phenyl-2-pyridylmethoxy)-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR114##

(a) There was stirred at 120° C. for 4 hours a mixture of 6.74 g ofphenyl-2-pyridylmethanol, 7.85 g of4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine, 11.0 g of concentratedsulfuric acid and 15 ml of toluene. After cooling, the reaction solutionwas poured into ice water, made alkaline with an aqueous sodiumhydroxide, and extracted with toluene. The extract was washed withwater, and toluene was removed under reduced pressure. The residue waseluted with ethyl acetate-ethanol-dichloromethane (1:1:1) by silica gelcolumn chromatography to give 3.67 g of oily4-(phenyl-2-pyridylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.60-2.05 (6H,m), 2.14 (2H,m), 2.51 (2H,t), 2.75(2H,m), 3.47 (1H,m), 4.15 (2H,t), 5.64 (1H,s), 6.92-7.87 (12H,m), 8.51(1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-(phenyl-2-pyridylmethoxy)-1-[3-(2-aminophenoxy)propyl]piperidine.

(c) Into 25 ml of dichloromethane were dissolved 2.0 g of the aminocompound obtained in (b) and 1.1 g of pyridine, and 0.66 g ofmethanesulfonyl chloride was added dropwise to the resultant solutionwith ice cooling, followed by stirring for 1 hour. The reaction solutionwas poured into ice water, and extracted with ethyl acetate. The extractwas washed with water, and ethyl acetate was removed. The residue waseluted with ethanol-dichloromethane (1:5) by silica gel columnchromatography to give 1.78 g of the desired compound.

¹ H-NMR (CDCl₃) δ:1.65-1.83 (2H,m), 1.84-2.03 (4H,m), 2.17 (2H,m), 2.49(2H,t), 2.75 (2H,m), 2.94 (3H,s), 3.50 (1H,m), 4.08 (2H,t) 5.64 (1H,s),6.88-7.71 (12H,m), 8.51 (1H,dd)

EXAMPLE 33 Preparation of4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR115##

(a) The procedure of Example 32 (a) was repeated except for using(4-chlorophenyl)-2-pyridylmethanol and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine instead ofphenyl-2-pyridylmethanol and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.60-2.30 (8H,m), 2.56 (2H,m), 2.79 (2H,m), 3.49(1H,m), 4.15 (2H,t), 5.59 (1H,s), 6.95-7.85(11H,m), 8.51 (1H,d)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-[3-(2-aminophenoxy)propyl]piperidine

¹ H-NMR (DMSO-d₆) δ:1.60-2.30 (8H,m), 2.57 (2H,t), 2.76 (2H,m), 3.49(1H,m), 3.82 (2H,br s), 4.03 (2H,t), 5.78 (1H,s), 6.50-6.85 (4H,m),7.30-7.93 (7H,m), 8.55 (1H,dd)

(c) The procedure of Example 32 (c) was repeated except for using theamino compound obtained in (b) instead of4-(phenyl-2-pyridylmethoxy)-1-[3-(2-aminophenoxy)propyl]piperidine togive the desired compound.

¹ H-NMR (CDCl₃) δ:1.63-1.82 (2H,m), 1.83-2.03 (4H,m), 2.17 (2H,m), 2.48(2H,t), 2.74 (2H,m), 2.94 (3H,s), 3.48 (1H,m), 4.08 (2H,t) 5.60 (1H,s),6.89-7.73 (11H,m), 8.51 (1H,br d)

EXAMPLE 34 Preparation of4-(phenyl-3-pyridylmethoxy)-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR116##

(a) The procedure of Example 24 (a) was repeated except for using4-(phenyl-3-pyridylmethoxy)piperidine and1-chloro-3-(2-nitrophenoxy)propane instead of4-[(2-chlorophenyl)-phenylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane to give oily4-(phenyl-3-pyridylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.60-1.78 (2H,m), 1.87 (2H,m), 1.99 (2H,qunit), 2.15(2H,m), 2.52 (2H,t), 2.76 (2H,m), 3.44 (1H,m), 4.16 (2H,t), 5.55 (1H,s),6.90-7.86 (11H,m), 8.49 (1H,br d), 8.60 (1H,br s)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-(phenyl-3-pyridylmethoxy)-1-[3-(2-aminophenoxy)propyl]piperidine.

(c) The procedure of Example 32 (c) was repeated except for using theamino compound obtained in (b) instead of4-(phenyl-2-pyridylmethoxy)-1-[3-(2-aminophenoxy)propyl]piperidine togive the desired compound.

¹ H-NMR (CDCl₃) δ:1.63-2.07 (6H,m), 2.10-2.30 (2H,m), 2.51 (2H,br t),2.76 (2H,m), 2.95 (3H,s), 3.48 (1H,m), 4.09 (2H,t), 5.55 (1H,s)6.87-7.67(11H,m), 8.50 (1H,br d), 8.60 (1H,s)

EXAMPLE 35 Preparation of4-(phenyl-4-pyridylmethoxy)-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidineR1 ? ##STR117##

(a) The procedure of Example 24 (a) was repeated except for using4-(phenyl-4-pyridylmethoxy)piperidine and1-chloro-3-(2-nitrophenoxy)propane instead of4-[(2-chlorophenyl)-phenylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane to give oily4-(phenyl-4-pyridylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.60-2.08 (6H,m), 2.15 (2H,m), 2.53 (2H,t), 2.76(2H,m), 3.43 (1H,m), 4.16 (2H,t), 5.47 (1H,s), 6.95-7.56 (10H,m), 7.81(1H,dd), 8.53 (2H, d)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-(phenyl-4-pyridylmethoxy)-1-[3-(2-aminophenoxy)propyl]piperidine.

(c) The procedure of Example 32 (c) was repeated except for using theamino compound obtained in (b) instead of4-(phenyl-2-pyridylmethoxy)-1-[3-(2-aminophenoxy)propyl]piperidine togive the desired compound.

¹ H-NMR (CDCl₃) δ:1.65-2.06 (6H,m), 2.23 (2H,m), 2.52 (2H,br t), 2.77(2H,m), 2.95 (3H,s), 3.47 (1H,m), 4.09 (2H,t), 5.47 (1H,s), 6.85-7.55(11H,m), 8.54 (2H,d)

EXAMPLE 36 Preparation of4-(phenyl-2-thienylmethoxy)-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR118##

(a) Into 50 ml of methyl isobutyl ketone were dissolved 5.0 g ofphenyl-2-thienylmethyl chloride, 8.1 g of4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine and 7.3 g oftriethylamine, and the resultant solution was heated under reflux withstirring for 3 hours. After cooling, the reaction solution was washedwith water, and the solvent was removed under reduced pressure.

The residue was eluted with ethyl acetate-ethanoldichloromethane (1:1:1)by silica gel column chlomatography to give 8.46 g of4-(phenyl-2-thienylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidinehydrochloride.

¹ H-NMR (CDCl₃) δ:1.80-2.07 (2H,m), 2.11-2.44 (4H,m), 2.80-3.20 (6H,m),3.77 (1H,m), 4.25 (2H,t), 5.68 (1H,s), 6.72-7.59 (11H,m), 7.85 (1H,dd)

In 20 ml of 5% aqueous sodium carbonate solution was suspended 1.0 g ofthe hydrochloride obtained in the above. The resultant solution wasextracted with ethyl acetate and the organic layer was washed withwater. The solvent was removed under reduced pressure to give 0.83 g ofoily 4-(phenyl-2-thienylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.59-2.07 (6H,m), 2.08-2.30 (2H,m), 2.54 (2H,t), 2.78(2H,m), 3.51 (1H,m), 4.16 (2H,t), 5.72 (1H,s), 6.71-7.55 (11H,m), 7.81(1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-(phenyl-2-thienylmethoxy)-1-[3-(2-aminophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.57-2.37 (8H,m), 2.54 (2H,t), 2.66-2.88 (2H,m), 3.52(1H,m), 3.81 (2H,br s), 4.03 (2H,t), 5.72 (1H,s), 6.59-7.47 (12H,m)

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine, and the crudeproduct thus obtained was eluted with ethylacetate-ethanol-dichloromethane (5:1:3) by silica gel columnchromatography to give the desired compound.

m.p.: 102°-104.5° C. (recrystallized from ethyl acetate-n-hexane)

¹ H-NMR (CDCl₃) δ:1.63-2.05 (6H,m), 2.11-2.31 (2H,m), 2.50 (2H,t), 2.75(2H,m), 2.94 (3H,s) 3.52 (1H,m), 4.09 (2H,t), 5.72 (1H,s), 6.72-7.56(12H,m)

The procedure of Example 3 was repeated except for using the desiredcompound obtained in the above and fumaric acid instead of4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidineand fumaric acid to give the fumarate of the desired compound.

m.p.: 165°-168° C. (recrystallized from isopropyl alcohol)

The procedure of Example 3 was repeated except for using the desiredcompound obtained in the above and oxalic acid instead of4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidineand fumaric acid to give the oxalate of the desired compound.

m.p.: 186°-189° C. (recrystallized from methanol)

EXAMPLE 37 Preparation of4-(phenyl-2-thienylmethoxy)-1-[3-(2-methanesulfonylaminophenoxy)-1-methylpropyl]piperidine##STR119##

(a) The procedure of Example 36 (a) was repeated except for usingphenyl-2-thienylmethyl chloride and4-hydroxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine instead ofphenyl-2-thienylmethyl chloride and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-(phenyl-2-thienylmethoxy)-1-[3-(2-nitrophenoxy)-1-methylpropyl]piperidine.

¹ H-NMR (CDCl₃) δ:0.98 (3H,d), 1.50-2.07 (6H,m), 2.07-2.23 (1H,m),2.28-2.45 (1H,m), 2.58-2.97 (3H,m), 3.43 (1H,m), 4.06-4.28 (2H,m), 5.73(1H,s), 6.71-7.55 (11H,m), 7.80 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-(phenyl-2-thienylmethoxy)-1-[3-(2-aminophenoxy)-1-methylpropyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.00 (3H,d), 1.55-2.09 (6H,m), 2.12-2.28 (1H,m),2.30-2.46 (1H,m), 2.63-2.97 (3H,m), 3.46 (1H,m), 3.82 (2H,br s),3.93-4.18 (2H,m), 5.73 (1H,s), 6.62-6.96 (6H,m), 7.20-7.47 (6H,m)

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

m.p.: 100°-102.5° C.

¹ H-NMR (CDCl₃) δ:1.00 (3H,d), 1.55-2.07 (6H,m), 2.12-2.28 (1H,m),2.34-2.50 (1H,m), 2.61-2.93 (3H,m), 2.94 (3H,s) 3.47 (1H,m), 4.00-4.20(2H,m), 5.73 (1H,s), 6.72-7.57 (12H,m)

EXAMPLE 38 Preparation of4-(phenyl-2-thienylmethoxy)-1-[3-(2-methanesulfonylaminophenoxy)-3-methylpropyl]piperidine##STR120##

(a) The procedure of Example 36 (a) was repeated except for usingphenyl-2-thienylmethyl chloride and4-hydroxy-1-[3-methyl-3-(2-nitrophenoxy)propyl]piperidine instead ofphenyl-2-thienylmethyl chloride and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-(phenyl-2-thienylmethoxy)-1-[3-(2-nitrophenoxy)-3-methylpropyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.35 (3H,d), 1.55-2.29 (8H,m), 2.44 (2H,m), 2.60-2.84(2H,m), 3.48 (1H,m), 4.63 (1H,m), 5.72 (1H,s) 6.72-7.52 (11H,m), 7.74(1H,d)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-(phenyl-2-thienylmethoxy)-1-[3-(2-aminophenoxy)-3-methylpropyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.31 (3H,d), 1.62-2.04 (6H,m), 2.23 (2H,m), 2.34-2.58(2H,m), 2.75 (2H,m), 2.95 (3H,s), 3.52 (1H,m) 4.50 (1H,m), 5.71 (1H,s)6.72-7.55 (12H,m)

EXAMPLE 39 Preparation of4-(phenyl-2-thienylmethoxy)-1-[4-(2-methanesulfonylaminophenoxy)-2(E)-butenyl]piperidine##STR121##

(a) Into 20 ml of methyl isobutyl ketone were dissolved 2.09 g ofphenyl-2-thienylmethyl chloride, 3.50 g of4-hydroxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine and 1.94 g ofN,N-diisopropylethylamine, and the resultant solution was heated underreflux with stirring for 2 hours. After cooling, the reaction solutionwas washed with water, and the solvent was removed under reducedpressure. The residue was eluted with ethanol-chloroform (1:50) bysilica gel column chromatography to give 3.06 g of oily4-(phenyl-2-thienylmethoxy)-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine.

¹ H-NMR (CDCl₃) δ: 1.61-2.32 (6H,m), 2.72 (2H,m), 3.02 (2H,d), 3.50(1H,m), 4.67 (2H,d), 5.71 (1H,s), 5.75-6.01 (2H,m) 6.70-7.54 (11H,m),7.82 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-(phenyl-2-thienylmethoxy)-1-[4-(2-aminophenoxy)-2(E)-butenyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

m.p.: 114°-117° C.

¹ H-NMR (CDCl₃) δ: 1.63-2.00 (4H,m), 2.10-2.30 (2H,m), 2.73 (2H,m), 2.94(3H,s), 3.03 (2H,d), 3.51 (1H,m), 4.58 (2H,d), 5.72 (1H,s) 5.75-5.97(2H,m), 6.73-7.58 (12H,m)

EXAMPLE 40 Preparation of4-(phenyl-2-thienylmethoxy)-1-[4-(2-methanesulfonylaminophenoxy)-2(Z)-butenyl]piperidine##STR122##

(a) The procedure of Example 39 (a) was repeated except for usingphenyl-2-thienylmethyl chloride and4-hydroxy-1-[4-(2-nitrophenoxy)-2(Z)-butenyl]piperidine instead ofphenyl-2-thienylmethyl chloride and4-hydroxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine to give oily4-(phenyl-2-thienylmethoxy)-1-[4-(2-nitrophenoxy)-2(Z)-butenyl]piperidine.

¹ H-NMR (CDCl₃) δ: 1.60-2.00 (4H,m), 2.05-2.34 (2H,m), 2.74 (2H,m), 3.06(2H,d), 3.52 (1H,m), 4.76 (2H,d), 5.72 (1H,s) 5.73-5.92 (2H,m),6.70-7.57 (11H,m), 7.81 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-(phenyl-2-thienylmethoxy)-1-[4-(2-aminophenoxy)-2(Z)-butenyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

m.p.: 99°-103° C.

¹ H-NMR (CDCl₃) δ: 1.63-2.03 (4H,m), 2.12-2.37 (2H,m), 2.73 (2H,m), 2.93(3H,s), 3.05 (2H,d), 3.53 (1H,m), 4.66 (2H,d), 5.72 (1H,s), 5.73-5.93(2H,m), 6.68-7.62 (12H,m)

EXAMPLE 41 Preparation of4-(phenyl-3-thienylmethoxy)-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR123##

(a) The procedure of Example 36 (a) was repeated except for usingphenyl-3-thienylmethyl chloride and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine instead ofphenyl-2-thienylmethyl chloride and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-(phenyl-3-thienylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidinehydrochloride.

¹ H-NMR (CDCl₃) δ: 1.82-2.07 (2H,m), 2.13-2.48 (4H,m), 2.83-3.23 (6H,m),3.74 (1H,m), 4.25 (2H,t), 5.53 (1H,s), 6.90-7.61 (11H,m), 7.85 (1H,dd)

The hydrochloride obtained in the above was treated with 5% aqueoussodium carbonate in the same way as in Example 36 (a) to give oily4-(phenyl-3-thienylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ: 1.62-2.10 (6H,m), 2.22 (2H,m), 2.56 (2H,t), 2.80(2H,m), 3.46 (1H,m), 4.17 (2H,t), 5.57 (1H,s) 6.94-7.56 (11H,m), 7.81(1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-(phenyl-3-thienylmethoxy)-1-[3-(2-aminophenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thehydrochloride of the desired compound.

m.p.: 175.5°-178° C. (recrystallized from ethanol-n-hexane)

¹ H-NMR (CDCl₃) δ: 1.80-2.55 (6H,m), 3.03 (3H,s), 3.18 (2H,m), 3.31(2H,t), 3.46 (2H,m), 3.81 (1H,m), 4.13 (2H,t), 5.49 (1H,s), 6.81-7.49(12H,m), 7.74 (1H,br s)

The hydrochloride obtained in the above was treated with 5% aqueoussodium carbonate to give the desired compound.

m.p.: 79.5°-82° C. (recrystallized from dichloromethane-n-hexane)

¹ H-NMR (CDCl₃) δ: 1.63-2.05 (6H,m), 2.19 (2H,m), 2.49 (2H,t), 2.77(2H,m), 2.94 (3H,s), 3.46 (1H,m), 4.08 (2H,t), 5.57 (1H,s), 6.89-7.41(11H,m), 7.51 (1H,dd)

EXAMPLE 42 Preparation of4-di(2-thienyl)methoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR124##

(a) The procedure of Example 36 (a) was repeated except for usingdi(2-thienyl)methyl chloride and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine instead ofphenyl-2-thienylmethyl chloride and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-di(2-thienyl)methoxy-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ: 1.62-1.83 (2H,m), 1.88 (2H,m), 2.01 (2H,quint), 2.22(2H,m), 2.55 (2H,t), 2.78 (2H,m), 3.58 (1H,m) 4.17 (2H,t), 5.98 (1H,s),6.83-7.57 (9H,m), 7.81 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-di(2-thienyl)methoxy-1-[3-(2-aminophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ: 1.67-1.84 (2H,m), 1.85-2.09 (4H,m), 2.28 (2H,m), 2.56(2H,t), 2.79 (2H,m), 3.60 (1H,m), 3.83 (2H,br s) 4.03 (2H,t), 5.97(1H,s) 6.63-7.00 (8H,m) 7.28 (2H,dd)

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine, and the crudeproduct thus obtained was eluted with ethylacetate-ethanol-dichloromethane (5:1:3) by silica gel columnchromatography to give the desired compound.

¹ H-NMR (CDCl₃) δ: 1.68-2.10 (6H,m), 2.32 (2H,m), 2.55 (2H,t), 2.78(2H,m), 2.95 (3H,s), 3.62 (1H,m), 4.10 (2H,t), 5.97 (1H,s), 6.86-7.35(9H,m), 7.52 (1H,dd)

EXAMPLE 43 Preparation of4-[(2-thienyl)-3-thienylmethoxy]-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR125##

(a) Into 50 ml of 1,2-dichloroethane were dissolved 4.29 g of(2-thienyl)-3-thienylmethyl chloride, 6.72 g of4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine and 3.88 g ofN,N-diisopropylethylamine, and the resultant solution was heated underreflux with stirring for 48 hours.

After cooling, the reaction solution was washed with water, and thesolvent was removed under reduced pressure. The residue was eluted withethyl aceate-ethanol-dichloromethane (1:1:1) by silica gel columnchromatography to give 5.51 g of4-[(2-thienyl)-3-thienylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidinehydrochloride.

¹ H-NMR (CDCl₃) δ: 1.96 (2H,m), 2.18-2.48 (4H,m), 2.97-3.23 (6H,m), 3.81(1H,m) 4.26 (2H,t), 5.78 (1H,s) 6.82-7.60 (9H,m), 7.84 (1H,d)

The hydrochloride obtained in the above was treated with 5% aqueoussodium carbonate to give oily4-[(2-thienyl)-3-thienylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ: 1.60-1.80 (2H,m), 1.81-2.28 (6H,m), 2.53 (2H,t), 2.77(2H,m), 3.51 (1H,m), 4.16 (2H,t), 5.81 (1H,s), 6.83-7.56 (9H,m), 7.81(1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-[(2-thienyl)-3-thienylmethoxy]-1-[3-(2-aminophenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ: 1.65-2.16 (6H,m), 2.20-2.48 (2H,m), 2.60 (2H,m), 2.81(2H,m), 2.97 (3H,s), 3.59 (1H,m), 4.11 (2H,t), 5.80 (1H,s), 6.80-7.33(9H,m), 7.51 (1H,dd)

EXAMPLE 44 Preparation of4-di(3-thienyl)methoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR126##

(a) The procedure of Example 36 (a) was repeated except for usingdi(3-thienyl)methyl chloride and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine instead ofphenyl-2-thienylmethyl chloride and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-di(3-thienyl)methoxy-1-[3-(2-nitrophenoxy)propyl]piperidinehydrochloride.

The obtained hydrochloride was treated with 5% aqueous sodium carbonateto give oily4-di(3-thienyl)methoxy-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ: 1.61-1.80 (2H,m), 1.81-1.97 (2H,m), 2.02 (2H,quint),2.21 (2H,m), 2.56 (2H,t), 2.79 (2H,m), 3.46 (1H,m), 4.17 (2H,t), 5.65(1H,s), 6.95-7.57 (9H,m), 7.82 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thehydrochloride of the nitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-di(3-thienyl)methoxy-1-[3-(2-aminophenoxy)propyl]piperidinehydrochloride.

m.p.: 179.5°-180° C. (recrystallized from ethanol-n-hexane)

¹ H-NMR (CDCl₃) δ: 1.95 (2H,br d), 2.35-2.55 (4H,m), 3.09 (2H,br t),3.28 (2H,m), 3.48 (2H,br d), 3.87 (1H,m), 4.11 (2H,t), 5.58 (1H,s),6.68-7.35 (10H,m)

The hydrochloride obtained in the above was treated with 5% aqueoussodium carbonate to give4-di(3-thienyl)methoxy-1-[3-2-aminophenoxy)propyl]piperdine.

m.p.: 80°-82° C. (recrystallized from ethyl acetate-n-hexane)

¹ H-NMR (CDCl₃) δ:1.77 (2H,m), 1.87-2.18 (4H,m), 2.37 (2H,m), 2.64(2H,t), 2.84 (2H,m), 3.52 (1H,m), 3.80 (2H,br s), 4.03 (2H,t), 5.64(1H,s) 6.62-7.35 (10H,m)

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thehydrochloride of the desired compound.

m.p.: 188.5°-190.5° C. (recrystallized from ethanol-n-hexane)

¹ H-NMR (CDCl₃) δ:1.84-2.06 (2H,m), 2.15-2.52 (4H,m), 3.03 (3H,s),3.05-3.38 (6H,m), 3.76 (1H,m), 4.13 (2H,t), 5.59 (1H,s), 6.82-7.51(10H,m)

The hydrochloride obtained in the above was treated with 5% aqueoussodium carbonate to give the desired compound.

m.p.: 92°-94° C. (recrystallized from ethyl acetate-n-hexane)

¹ H-NMR (CDCl₃) δ:1.63-1.80 (2H,m), 1.83-2.07 (4H,m), 2.22 (2H,m), 2.51(2H,t), 2.77 (2H,m), 2.95 (3H,s), 3.48 (1H,m), 4.09 (2H,t), 5.65 (1H,s),6.90-7.33 (9H,m), 7.52 (1H,dd)

The procedure of Example 3 was repeated except for using the desiredcompound obtained in the above and fumaric acid instead of4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidineand fumaric acid to give the fumarate of the desired compound.

m.p.: 118.5°-120.5° C. (recrystallized from dichloromethane-ethylacetate)

The procedure of Example 3 was repeated except for using the desiredcompound obtained in the above and oxalic acid instead of4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidineand fumaric acid to give the oxalate of the desired compound.

m.p.: 168.5°-171° C. (recrystallized from dichloromethane-ethanol)

EXAMPLE 45 Preparation of4-di(3-thienyl)methoxy-1-[3-(2-methanesulfonylaminophenoxy)-1-methylpropyl]piperidine##STR127##

(a) The procedure of Example 36 (a) was repeated except for usingdi(3-thienyl)methyl chloride and4-hydroxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine instead ofphenyl-2-thienylmethyl chloride and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-di(3-thienyl)methoxy-1-[1-methyl-3-(2-nitrophenoxy)propyl]piperidine

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-di(3-thienyl)methoxy-1-[3-(2-aminophenoxy)-1-methylpropyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.02 (3H,d), 1.56-2.13 (6H,m), 2.25 (1H,m), 2.45(1H,br t), 2.62-2.98 (3H,m), 2.95 (3H,s), 3.44 (1H,m), 4.00-4.21 (2H,m),5.65 (1H,s), 6.89-7.33 (9H,m), 7.51 (1H,dd)

EXAMPLE 46 Preparation of4-di(3-thienyl)methoxy-1-[4-(2-methanesulfonylaminophenoxy)-2(E)-butenyl]piperidine##STR128##

(a) The procedure of Example 39 (a) was repeated except for usingdi(3-thienyl)methyl chloride and4-hydroxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine instead ofphenyl-2-thienylmethyl chloride and4-hydroxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine to give oily4-di(3-thienyl)methoxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.59-1.79 (2H,m), 1.79-1.96 (2H,m), 2.14 (2H,m), 2.72(2H,m), 3.01 (2H,d), 3.44 (1H,m), 4.67 (2H,d), 5.64 (1H,s), 5.74-6.02(2H,m), 6.92-7.57 (9H,m), 7.82 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-di(3-thienyl)methoxy-1-[4-(2-aminophenoxy)-2(E)-butenyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.58-2.00 (4H,m), 2.17 (2H,m), 2.71 (2H,m), 3.00(2H,d), 3.46 (1H,m), 4.52 (2H,d), 5.63 (1H,s), 5.72-5.97 (2H,m),6.72-7.34 (10H,m)

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.63-1.98 (4H,m), 2.23 (2H,m), 2.75 (2H,m), 2.95(3H,s), 3.06 (2H,d), 3.48 (1H,m), 4.58 (2H,d), 5.64 (1H,s), 5.74-5.99(2H,m), 6.83-7.33 (9H,m) 7.52 (1H,dd)

EXAMPLE 47 Preparation of4-di(3-thienyl)methoxy-1-[4-(2-methanesulfonylaminophenoxy)-2(Z)-butenyl]piperidine##STR129##

(a) The procedure of Example 39 (a) was repeated except for usingdi(3-thienyl)methyl chloride and4-hydroxy-1-[4-(2-nitrophenoxy)-2(Z)-butenyl]piperidine instead ofphenyl-2-thienylmethyl chloride and4-hydroxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine to give oily4-di(3-thienyl)methoxy-1-[4-(2-nitrophenoxy)-2(Z)-butenyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.60-1.98 (4H,m), 2.24 (2H,m), 2.76 (2H,m), 3.11(2H,br d), 3.48 (1H,m), 4.76 (2H,d), 5.64 (1H,s), 5.71-5.93 (2H,m),6.92-7.57 (9H,m), 7.82 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)-propyl]piperidine to give4-di(3-thienyl)methoxy-1-[4-(2-aminophenoxy)-2(Z)-butenyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thehydrochloride of the desired compound.

¹ H-NMR (CDCl₃) δ:1.73-1.93 (2H,m), 2.09 (2H,m), 2.64 (2H,m), 2.89(2H,m), 2.98 (3H,s), 3.32 (2H,d), 3.62 (1H,m), 4.70 (2H,d), 5.62 (1H,s),5.82-6.04 (2H,m), 6.85-7.34 (9H,m), 7.51 (1H,dd)

The hydrochloride obtained in the above was treated with 5% aqueoussodium carbonate to give the desired compound.

¹ H-NMR (CDCl₃) δ:1.65-1.82 (2H,m), 1.83-1.97 (2H,m), 2.24 (2H,m), 2.75(2H,m), 2.94 (3H,s), 3.08 (2H,br d), 3.49 (1H,m), 4.66 (2H,d), 5.64(1H,s), 5.82 (2H,m) 6.87-7.33 (9H,m), 7.53 (1H,dd)

EXAMPLE 48 Preparation of4-[(3-pyridyl)-2-thienylmethoxy]-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR130##

(a) The procedure of Example 24 (a) was repeated except for using4-[(3-pyridyl)-2-thienylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane instead of4-[(2-chlorophenyl)-phenylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane to give oily4-[(3-pyridyl)-2-thienylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.72 (2H,m), 1.82-2.11 (4H,m), 2.30 (2H,m), 2.60(2H,t), 2.78 (2H,m), 3.51 (1H,m), 4.17 (2H,t), 5.78 (1H,s), 6.77-7.34(6H,m), 7.50 (1H,td) 7.72 (1H,br d), 7.82 (1H,dd), 8.55 (1H,m), 8.61(1H,br s)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-[(3-pyridyl)-2-thienylmethoxy]-1-[3-(2-aminophenoxy)propyl]piperidine.

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.67-1.87 (2H,m), 1.88-2.10 (4H,m), 2.34 (2H,m), 2.57(2H,t), 2.70-2.89 (2H,m), 2.96 (3H,s), 3.58 (1H,m), 4.09 (2H,t), 5.77(1H,s), 6.80-7.34 (7H,m), 7.51 (1H,dd), 7.73 (1H,dt), 8.55 (1H,d), 8.65(1H,d)

EXAMPLE 49 Preparation of4-[(3-pyridyl)-3-thienylmethoxy]-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidine##STR131##

(a) The procedure of Example 24 (a) was repeated except for using4-[(3-pyridyl)-3-thienylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane instead of4-[(2-chlorophenyl)-phenylmethoxy]piperidine and1-chloro-3-(2-nitrophenoxy)propane to give oily4-[(3-pyridyl)-3-thienylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.72 (2H,m), 1.90 (2H,m), 2.02 (2H,quint), 2.22(2H,m), 2.56 (2H,t), 2.79 (2H,m), 3.46 (1H,m), 4.16 (2H,t), 5.62 (1H,s),6.93-7.35 (6H,m), 7.51 (1H,td) 7.68 (1H,dt), 7.81 (1H,dd), 8.52 (1H,dd),8.61 (1H,d)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-[(3-pyridyl)-3-thienylmethoxy]-1-[3-(2-aminophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.76 (2H,m), 1.84-2.11 (4H,m), 2.28 (2H,m), 2.58(2H,t), 2.80 (2H,m), 3.49 (1H,m), 4.03 (2H,t), 5.61 (1H,s), 6.63-6.83(4H,m), 6.97 (1H, dd), 7.14 (1H,d), 7.22-7.33 (2H,m), 7.67 (1H,dt), 8.53(1H,d), 8.61 (1H,s)

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.76 (2H,m), 1.85-2.12 (4H,m), 2.30 (2H,m), 2.56(2H,t), 2.79 (2H,m), 2.96 (3H,s), 3.50 (1H,m), 4.09 (2H,t), 5.61 (1H,s),6.85-7.35 (7H,m), 7.51 (1H,dd), 7.66 (1H,d), 8.54 (1H,br s), 8.62 (1H,brs)

EXAMPLE 50 Preparation of4-di(3-thienyl)methoxy-1-[3-(2-N-methyl-N-methanesulfonylaminophenoxy)propyl]piperidine##STR132##

The procedure of Example 8 was repeated except for using4-di(3-thienyl)methoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidineobtained in Example 44 (c) and methyl iodide instead of4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidineand methyl iodide to give the desired compound.

¹ H-NMR (CDCl₃) δ:1.67-1.84 (2H,m), 1.90-2.15 (4H,m), 2.37 (2H,m), 2.65(2H,t), 2.85 (2H,m), 2.95 (3H,s), 3.26 (3H,s), 3.53 (1H,m), 4.09 (2H,t),5.64 (1H,s), 6.91-7.37 (10H,m)

EXAMPLE 51 Preparation of4-di(3-thienyl)methoxy-1-[3-(2-methanesulfonylamino-4-methylphenoxy)propyl]piperidine##STR133##

(a) The procedure of Example 36 (a) was repeated except for usingdi(3-thienyl)methyl chloride and4-hydroxy-1-[3-(4-methyl-2-nitrophenoxy)propyl]piperidine instead ofphenyl-2-thienylmethyl chloride and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-di(3-thienyl)methoxy-1-[3-(4-methyl-2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.60-1.77 (2H,m), 1.79-2.05 (4H,m), 2.14 (2H,m), 2.33(3H,s), 2.51 (2H,t), 2.76 (2H,m), 3.44 (1H,m), 4.12 (2H,t), 5.65 (1H,s),6.92-7.34 (8H,m), 7.62 (1H,m)

(b) The procedure of Example 1 (b) was repeated except for using thenitro comound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-di(3-thienyl)methoxy-1-[3-(2-amino-4-methylphenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.61-1.80 (2H,m), 1.81-2.05 (4H,m), 2.16 (2H,m), 2.21(3H,s), 2.51 (2H,t), 2.77 (2H,m), 3.46 (1H,m), 3.77 (2H,br s), 3.99(2H,t), 5.65 (1H,s), 6.45-6.57 (2H,m), 6.68 (1H,d), 6.99-7.32 (6H,m)

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.63-1.79 (2H,m), 1.81-2.03 (4H,m), 2.17 (2H,m), 2.29(3H,s), 2.48 (2H,t), 2.75 (2H,m), 2.94 (3H,s), 3.46 (1H,m), 4.05 (2H,t),5.65 (1H,s), 6.78-7.36 (9H,m)

EXAMPLE 52 Preparation of4-di(3-thienyl)methoxy-1-[3-(2-methanesulfonylaminophenoxy)-2-methylpropyl]piperidine##STR134##

(a) The procedure of Example 36 (a) was repeated except for usingdi(3-thienyl)methyl chloride and4-hydroxy-1-[2-methyl-3-(2-nitrophenoxy)propyl]piperidine instead ofphenyl-2-thienylmethyl chloride and4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily4-di(3-thienyl)methoxy-1-[2-methyl-3-(2-nitrophenoxy)propyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.06 (3H,d), 1.55-1.75 (2H,m), 1.77-1.92 (2H,m),1.94-2.26 (4H,m), 2.30-2.46 (1H,m), 2.67 (1H,m), 2.80 (1H,m), 3.41(1H,m), 3.89-3.99 (1H,m), 4.08-4.18 (1H,m), 5.65 (1H,s), 6.92-7.55(9H,m), 7.82 (1H,dd)

(b) The procedure of Example 1 (b) was repeated except for using thenitro compound obtained in (a) instead of4-diphenylmethoxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give4-di(3-thienyl)methoxy-1-[3-(2-aminophenoxy)-2-methylpropyl]piperidine.

¹ H-NMR (CDCl₃) δ:1.05 (3H,d), 1.55-1.75 (2H,m), 1.77-1.92 (2H,m),1.98-2.24 (4H,m), 2.31-2.45 (1H,m), 2.61-2.83 (2H,m), 3.43 (1H,m),3.68-3.91 (3H,m), 3.92-4.01 (1H,m), 5.65 (1H,s), 6.64-7.31 (10H,m)

(c) The procedure of Example 1 (c) was repeated except for using theamino compound obtained in (b) instead of4-diphenylmethoxy-1-[3-(2-aminophenoxy)propyl]piperidine to give thedesired compound.

¹ H-NMR (CDCl₃) δ:1.02 (3H,d), 1.59-1.78 (2H,m), 1.84 (2H,m), 2.03-2.28(4H,m), 2.29-2.43 (1H,m), 2.67 (1H,m), 2.78 (1H,m), 2.94 (3H,s), 3.45(1H,m), 3.80-3.90 (1H,m), 3.99-4.08 (1H,m), 5.65 (1H,s), 6.90-7.31(9H,m), 7.52 (1H,dd)

That the piperidine derivative of the present invention has theexcellent inhibitory activity of histamine release and antihistaminicactivity and that the piperidine derivative of the present invention istherapeutically effective for ischemic heart disease such as stenocardiaor myocardial infarction are illustrated with reference to followingTest Examples.

TEST EXAMPLE 1 Inhibition of anaphylactic histamine release

Hartley male guinea pigs weighing about 450 g which were passivelysensitized with an anti-DNP-egg albumin guinea pig serum were killedwith a thiopentbarbital anesthetia. Their lungs were perfused by way ofthe pulmonary artery with a Tyrode's solution. The lungs were removedand fragmented. A definite weight of 100 mg lung fragments, which wasdistributed into individual tubes and suspended in 1 ml of Tyrode'ssolution, was challenged with the antigen (DNP-egg albumin, finalconcentration: 0.3 μg/ml) at 37° C. for 15 min. The test compoundsobtained in Example, which were dissolved or suspended in Tyrode'ssolution, were added 10 min before antigen challenge. The reaction wasstopped by immersing in ice cold water, and then centrifuged. The amountof histamine in the supernatant fluid was measured by using fluoremetricmethod according to Shore et al.

From the results described above, an inhibition ratio was calculated asfollows and a 25%-inhibitory concentration was obtained: ##EQU1## A:amount of histamine released by the antigen stimulation in the presenceof a compound of the present invention

B: amount of histamine released spontaneously

C: amount of histamine released by the antigen stimulation.

The results are shown in Table 3.

TEST EXAMPLE 2 Antihistaminic activity

Hartley male guinea pigs weighing 500-600 g were used. Isolated trachealsmooth muscle chain strips were prepared by a usual method and suspendedin 2 ml organ bath of Tyrode's solution aerated with 95% O₂.5 % CO₂ at37° C. Each strip was attached to an isotonic transducer (made by NihonKoden Kogyo KK) with a load of 0.5 g. After almost constant contraction,histamine was added cumulatively, until maximum constriction wasobtained. The constriction of tracheal strip was recorded by Servocorder(made by Giraphtec KK). The strip was washed with Tyrode's solution andallowed to stabilize. Test compound was to the bath 5 min prior to theaddition of histamine and the response curve to the histamine wasrepeated. The pA₂ values were calculated using the techniques of VanRossum.

The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                                      Test Example 1 Test Example 2                                   Test Compound (25%-inhibitory conc.)                                                                       (pA.sub.2)                                       ______________________________________                                        Example 1     1 × 10.sup.-6 M                                                                        8.7                                              Example 34 (fumarate)                                                                       1 × 10.sup.-6 M                                                                        9.9                                              Example 36 (fumarate)                                                                       1 × 10.sup.-7 M                                                                        8.6                                              Example 37    1 × 10.sup.-7 M                                                                        8.4                                              Example 40    1 × 10.sup.-7 M                                                                        8.2                                              Example 44 (fumarate)                                                                       3 × 10.sup.-8 M                                                                        8.6                                              Amlexanox*    3 × 10.sup.-5 M                                                                        --                                               Oxatomide*    1 × 10.sup.-4 M                                                                        8.9                                              Diphenhyldramine                                                                            --             8.9                                              hydrochloride*                                                                ______________________________________                                         *Reference drug                                                          

In Test Examples 1 and 2, comparative tests were carried out by using asreference drugs, Amlexanox having the inhibitory activity of histaminerelease and Oxatomide having the inhibitory activity of histaminerelease and antihistaminic activity and diphenhydramine hydrochloridehaving antihistaminic activity.

From the results described in Table 3, the compounds of the presentinvention were confirmed to have both excellent inhibitory activity ofanaphylactic histamine release and antihistaminic activity.

TEST EXAMPLE 3

Hearts were isolated from Std; Wistar male rats weighing 200-300 g (9-10weeks old). The hearts were perfused using Langendorff's apparatus at aflow rate of 8 ml/min. As a perfusate, Krebs-Henseleit-bicarbonatesolution (37° C., pH 7.4) containing 11 mM glucose, oxygenated with amixed gas of 95% O₂ and 5% CO₂ was used. The heart was preloaded with aninitial resting tension of 2.0 g and paced at 200-300 beats min⁻¹. Afterthe hearts were allowed to be stable for 30-60 minutes, 0.1 ml of asolution of each test compound in 10% DMSO was added thereto to be aconcentration of 0.1, 1.0, 10 or 100 μg of each compound per heart.

Myocardial contractile force was isometrically measured by means of aforce-displacement transducer (Type: TB-612T, made by Nihon Kohden KogyoKK) connected to the apex of the heart through a thread. Coronaryperfusion pressure was monitored by an electric manometer (Type:MPU-0.5, made by Nihon Kohden Kogyo KK) connected to a side branch ofthe aortic cannule.

From these results, change rates were calculated according to thefollowing expression. ##EQU2## A: value before adding a test compound B:value after adding a test compound

The results are shown in Table 4.

                                      TABLE 4                                     __________________________________________________________________________    Test       Concentration                                                                         Perfusion pressure                                                                     Contractive force                                                                      Heart rate                               compound   (μg/heart)                                                                         (Δ %)                                                                            (Δ %)                                                                            (Δ %)                              __________________________________________________________________________    Example 1  0.1     -8.39 ± 3.4                                                                          2.0 ± 3.6                                                                           0.7 ± 1.2                                       1       -24.8 ± 3.0**                                                                       11.9 ± 2.4                                                                          -0.7 ± 1.2                                       10      -42.9 ± 3.2**                                                                       11.8 ± 2.3                                                                          -0.7 ± 1.2                                       100     -49.0 ± 4.8**                                                                       -25.0 ± 6.8**                                                                        -16.6 ± 15.6**                       Example 33 0.1     -7.0 ± 6.1                                                                           5.0 ± 4.3                                                                          -1.2 ± 2.1                                       1       -19.2 ± 2.2**                                                                       13.3 ± 1.9                                                                          -1.9 ± 1.8                                       10      -39.1 ± 5.4**                                                                       16.0 ± 4.5                                                                          -4.6 ± 4.7                                       100     -40.1 ± 5.2**                                                                        -46.2 ± 13.4**                                                                      -17.2 ± 10.1**                       Example 44 0.1     -6.0 ± 13.7                                                                          8.8 ± 2.5                                                                          -5.7 ± 1.4                                       1       -28.9 ± 3.0**                                                                        19.1 ± 5.7**                                                                       -3.6 ± 4.1                                       10      -47.9 ± 4.8**                                                                        16.2 ± 11.3                                                                        -6.3 ± 1.5                                       100     -55.8 ± 3.5**                                                                        -46.3 ± 19.4**                                                                      -59.9 ± 11.1**                       Control drug                                                                             0.1     -10.3 ± 4.0                                                                          3.5 ± 6.9                                                                          -2.7 ± 1.8                            Diltiazem  1       -32.1 ± 6.9**                                                                        7.0 ± 16.1                                                                         -3.5 ± 2.4                            hydrochloride                                                                            10      -47.1 ± 1.4**                                                                        -67.1 ± 17.5**                                                                      -25.9 ± 30.3**                                  100     -48.8 ± 1.4**                                                                       -86.5 ± 7.0**                                                                        -71.4 ± 11.9**                       Control (10% DMSO) -7.1 ± 4.6                                                                           8.8 ± 4.6                                                                          -1.5 ± 2.4                            __________________________________________________________________________     means value ± S.D., n = 3-4 (n = 30 in control (10% DMSO))                 **p <0.01 significant difference from control (10% DMSO)                 

The compounds obtained in Examples caused lowerings of perfusionpressure at dosages which do not cause changes of contractive force orheart rates in contrast with diltiazem hydrochloride.

While diltiazem hydrochloride caused significant lowerings ofcontractive force and heart rates at a dosage of 10 μg/heart, thecompounds obtained in Examples did not cause any changes at a dosage of10 μg/heart. Therefore, the compounds of the present invention arerecognized to be safe in wider range of dosage.

From the results as described above, the compounds of the presentinvention were confirmed to be effective for prevention or treatment ofischemic heart disease such as stenocardia or myocardial infarction.

TEST EXAMPLE 4

The LD₅₀ of the compounds obtained in Examples 1, 34, 37, 40 and 44 weremore than 500 mg/kg when these compounds were given orally to miceweighing 22-27 g (ddY, male, 5 weeks).

Formulation Examples of the compounds of the present invention areillustrated below, but it should be construed that the formulation usingthe compounds of the present invention are not limited to theseExamples.

FORMULATION EXAMPLE 1

Tablets each containing 10 mg of an effective ingredient were preparedaccording to the formulation described below.

    ______________________________________                                        (component)            (mg)                                                   ______________________________________                                        compound obtained in Example 44                                                                      10                                                     (fumarate)                                                                    lactose                30                                                     corn starch            40                                                     crystalline cellulose  15                                                     methyl cellulose        3                                                     magnesium stearate      2                                                     ______________________________________                                    

FORMULATION EXAMPLE 2

A component mixture in an amount of 100 mg containing 10 mg of aneffective ingredient according to the formulation described below wasencapsulated to give a capsule.

    ______________________________________                                        (component)            (mg)                                                   ______________________________________                                        compound obtained in Example 44                                                                      10                                                     (fumarate)                                                                    lactose                50                                                     corn starch            30                                                     crystalline cellulose   8                                                     magnesium stearate      2                                                     ______________________________________                                    

In addition to the ingredients used in the Examples, other ingredientscan be used as set forth in the specification to obtain substantiallythe same results.

What we claim is:
 1. A piperidine compound having the formula (I):##STR135## wherein R¹ and R², which may be the same or different fromeach other, are (i) a phenyl group or a phenyl group substituted by ahalogen atom, trifluoromethyl group, a C₁₋₅ alkyl group or a C₁₋₅alkoxyl group, (ii) a C₃₋₇ cycloalkyl group, (iii) pyridyl group or (iv)thienyl group, R³ is (i) hydrogen atom, (ii) a halogen atom, (iii) aC₁₋₄ alkyl group or (iv) a C₁₋₄ alkoxyl group, R⁴ is (i) hydrogen atomor (ii) a C₁₋₄ alkyl group. R⁵ is (i) a C₁₋₅ alkyl group or a C₁₋₅ alkylgroup substituted by a halogen atom, (ii) phenyl group or (iii) thienylgroup and Z is (i) a C₁₋₆ alkylene group, (ii) a C₂₋₆ alkenylene groupor (iii) a C₃₋₆ alkynylene group or a pharmacologically acceptable saltthereof.
 2. A piperidine compound having the formula (II): ##STR136##wherein R¹ and R², which may be the same or different from each other,are (i) a phenyl group or a phenyl group substituted by a halogen atom,trifluoromethyl group, a C₁₋₅ alkyl group or a C₁₋₅ alkoxyl group, (ii)a C₃₋₇ cycloalkyl group, (iii) pyridyl group or (iv) thienyl group, R³is (i) hydrogen atom, (ii) a halogen atom, (iii) a C₁₋₄ alkyl group or(iv) a C₁₋₄ alkoxyl group, and Z is (i) a C₁₋₆ alkylene group, (ii) aC₂₋₆ alkenylene group or (iii) a C₃₋₆ alkynylene group.
 3. A piperidinecompound having the formula (III): ##STR137## wherein R¹ and R², whichmay be the same or different from each other, are (i) a phenyl group ora phenyl group substituted by a halogen atom, trifluoromethyl group, aC₁₋₅ alkyl group or a C₁₋₅ alkoxyl group, (ii) a C₃₋₇ cycloalkyl group,(iii) pyridyl group or (iv) thienyl group, R³ is (1) hydrogen atom, (ii)a halogen atom, (iii) a C₁₋₄ alkyl group or (iv) a C₁₋₄ alkoxyl group,and Z is (i) a C₁₋₆ alkylene group, (ii) a C₂₋₆ alkenylene group or(iii) a C₃₋₆ alkynylene group.
 4. A piperidine compound of claim 1,which is4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidineor a pharmacologically acceptable salt thereof.
 5. A piperidine compoundof claim 1, which is4-(phenyl-2-thienylmethoxy)-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidineor a pharmacologically acceptable salt thereof.
 6. A piperidine compoundof claim 1, which is4-di(3-thienyl)methoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidineor a pharmacologically acceptable salt thereof.
 7. A piperidine compoundof claim 1, which is4-diphenylmethoxy-1-[3-(2-methanesulfonylaminophenoxy)propyl]piperidineor a pharmacologically acceptable salt thereof.
 8. A piperidine compoundof claim 1, which is4-di(3-thienyl)methoxy-1-[4-(2-methanesulfonylaminophenoxy)-2(Z)-butenyl]piperidineor a pharmacologically acceptable salt thereof.
 9. An anti-allergiccomposition agent comprising as an effective amount the piperidinecompound or a pharmacologically acceptable salt thereof of claim 1 incombination with a pharmaceutically acceptable carrier.
 10. Atherapeutic composition for ischemic heart disease comprising as aneffective amount the piperidine compound or a pharmacologicallyacceptable salt thereof of claim 1 in combination with apharmaceutically acceptable carrier.